Natural history of optic pathway gliomas in a cohort of unselected patients affected by Neurofibromatosis 1

Abstract

Optic pathway glioma (OPG) represents the most common central nervous system tumor in children with Neurofibromatosis type-1 (NF1). Although overall survival is usually good, no clear prognostic factors have been identified so far. We assessed the natural history of OPG in a cohort of unselected patients affected by NF1. We retrospectively evaluated 414 consecutive patients affected by NF1 and referred to our NF1 clinic before age 6. Average follow-up was 11.9 years: 52 out of 414 patients had OPG with a total cumulative incidence of 15.4% at age 15 (Kaplan–Meier estimate) and a statistically significant difference according to sex. Brain and orbit MRI was performed in 44.7% of patients: 34.6% for screening purposes and 65.4% because of the presence of neurological, ocular or other symptoms. OPG was diagnosed in 12.5% of cases in the first group, whereas in 36.4% in the latter group (p = 0.001). Clinical management was conservative in most patients, while 8 of them underwent therapy mainly because of visual deterioration. OPG was diagnosed earlier in treated patients, but the difference was not statistically significant. Conversely, all patients who underwent screening MRI had normal visual outcome. In conclusion, OPG location does not correlate with need for treatment; female patients were more frequently affected by OPG but not more frequently treated. OPG diagnosis by screening MRI does not affect the natural history of the tumor.

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Stereotactic radiosurgery for small brain metastases and implications regarding management with systemic therapy alone

Abstract

While stereotactic radiosurgery (SRS) has been shown effective in the management of brain metastases, small brain metastases (≤10 mm) can pose unique challenges. Our aim was to investigate the efficacy of SRS in the treatment of small brain metastases, as well as elucidate clinically relevant factors impacting local failure (LF). We utilized a large, single-institution cohort to perform a retrospective analysis of patients with brain metastases up to 1 cm in maximal dimension. Clinical and radiosurgical parameters were investigated for an association with LF and compared using a competing risk model to calculate cumulative incidence functions, with death and whole brain radiotherapy serving as competing risks. 1596 small brain metastases treated with SRS among 424 patients were included. Among these tumors, 33 developed LF during the follow-up period (2.4% at 12 months following SRS). Competing risk analysis demonstrated that LF was dependent on tumor size (0.7% if ≤2 mm and 3.0% if 2–10 mm at 12 months, p = 0.016). Other factors associated with increasing risk of LF were the decreasing margin dose, increasing maximal tumor diameter, volume, and radioresistant tumors (each p < 0.01). 22 tumors (0.78%) developed radiographic radiation necrosis following SRS, and this incidence did not differ by tumor size (≤2 mm and 2–10 mm, p = 0.200). This large analysis confirms that SRS remains an effective modality in treatment of small brain metastases. In light of the excellent local control and relatively low risk of toxicity, patients with small brain metastases who otherwise have a reasonable expected survival should be considered for radiosurgical management.

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G-1 Inhibits Breast Cancer Cell Growth via Targeting Colchicine-Binding Site of Tubulin to Interfere with Microtubule Assembly

G-protein–coupled estrogen receptor 1 (GPER1) has been reported to play a significant role in mediating the rapid estrogen actions in a wide range of normal and cancer cells. G-1 was initially developed as a selective agonist for GPER. However, the molecular mechanisms underlying the actions of G-1 are unknown, and recent studies report inconsistent effects of G-1 on the growth of breast cancer cells. By employing high-resolution laser scanning confocal microscopy and time-lapse imaging technology, as well as biochemical analyses, in the current study, we provide convincing in vitro and in vivo evidence that G-1 is able to suppress the growth of breast cancer cells independent of the expression status of GPERs and classic estrogen receptors. Interestingly, we found that triple-negative breast cancer cells (TNBC) are very sensitive to G-1 treatment. We found that G-1 arrested the cell cycle in the prophase of mitosis, leading to caspase activation and apoptosis of breast cancer cells. Our mechanistic studies indicated that G-1, similar to colchicine and 2-methoxyestradiol, binds to colchicine binding site on tubulin, inhibiting tubulin polymerization and subsequent assembly of normal mitotic spindle apparatus during breast cancer cell mitosis. Therefore, G-1 is a novel microtubule-targeting agent and could be a promising anti-microtubule drug for breast cancer treatment, especially for TNBC treatment. Mol Cancer Ther; 16(6); 1080–91. ©2017 AACR.

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Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53-Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death

Photodynamic therapy (PDT), using 5-aminolevulinic acid (ALA) to drive synthesis of protoporphryin IX (PpIX) is a promising, scar-free alternative to surgery for skin cancers, including squamous cell carcinoma (SCC) and SCC precursors called actinic keratoses. In the United States, PDT is only FDA approved for treatment of actinic keratoses; this narrow range of indications could be broadened if PDT efficacy were improved. Toward that goal, we developed a mechanism-based combination approach using 5-fluorouracil (5-FU) as a neoadjuvant for ALA-based PDT. In mouse models of SCC (orthotopic UV-induced lesions, and subcutaneous A431 and 4T1 tumors), pretreatment with 5-FU for 3 days followed by ALA for 4 hours led to large, tumor-selective increases in PpIX levels, and enhanced cell death upon illumination. Several mechanisms were identified that might explain the relatively improved therapeutic response. First, the expression of key enzymes in the heme synthesis pathway was altered, including upregulated coproporphyrinogen oxidase and downregulated ferrochelatase. Second, a 3- to 6-fold induction of p53 in 5-FU–pretreated tumors was noted. The fact that A431 contains a mutant form p53 did not prevent the development of a neoadjuvantal 5-FU effect. Furthermore, 5-FU pretreatment of 4T1 tumors (cells that completely lack p53), still led to significant beneficial inductions, that is, 2.5-fold for both PpIX and PDT-induced cell death. Thus, neoadjuvantal 5-FU combined with PDT represents a new therapeutic approach that appears useful even for p53-mutant and p53-null tumors. Mol Cancer Ther; 16(6); 1092–101. ©2017 AACR.

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PMP22 Regulates Self-Renewal and Chemoresistance of Gastric Cancer Cells

Cancer stem cells possess self-renewal and chemoresistance activities. However, the manner in which these features are maintained remains obscure. We sought to identify cell surface protein(s) that mark self-renewing and chemoresistant gastric cancer cells using the explorer antibody microarray. We identified PMP22, a target gene of the Wnt/β-catenin pathway, as the most upregulated cell surface protein in gastric cancer xenografts exposed to cisplatin (DDP). PMP22 expression was markedly upregulated in tumorspheric cells and declined with differentiation. Infecting gastric cancer cells with lentivirus expressing PMP22 shRNAs reduced proliferation, tumorsphere formation, and chemoresistance to cisplatin in vitro and in NOD/SCID mice. When combined with bortezomib, a PMP22 inhibitor, the chemotherapeutic sensitivity to cisplatin treatment was dramatically increased by inducing cell apoptosis in cultured cells and xenograft mouse models. Finally, mRNA expression levels of PMP22 were detected in 38 tumor specimens from patients who received six cycles of perioperative chemotherapy. A strong correlation between PMP22 level and tumor recurrence was revealed, thus showing a pivotal role of PMP22 in the clinical chemoresistance of gastric cancer. Our study is the first to show the role of PMP22 in gastric cancer stemness and chemoresistance and reveals a potential new target for the diagnosis and treatment of recurrent gastric cancer. Mol Cancer Ther; 16(6); 1187–98. ©2017 AACR.

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Biological Role and Therapeutic Targeting of TGF-{beta}3 in Glioblastoma

Transforming growth factor (TGF)-β contributes to the malignant phenotype of glioblastoma by promoting invasiveness and angiogenesis and creating an immunosuppressive microenvironment. So far, TGF-β₁ and TGF-β₂ isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma. A pathogenic role for TGF-β₃ in glioblastoma has not been defined yet. Here, we studied the expression and functional role of endogenous and exogenous TGF-β₃ in glioblastoma models. TGF-β₃ mRNA is expressed in human and murine long-term glioma cell lines as well as in human glioma-initiating cell cultures with expression levels lower than TGF-β₁ or TGF-β₂ in most cell lines. Inhibition of TGF-β₃ mRNA expression by ISTH2020 or ISTH2023, two different isoform-specific phosphorothioate locked nucleic acid (LNA)-modified antisense oligonucleotide gapmers, blocks downstream SMAD2 and SMAD1/5 phosphorylation in human LN-308 cells, without affecting TGF-β₁ or TGF-β₂ mRNA expression or protein levels. Moreover, inhibition of TGF-β₃ expression reduces invasiveness in vitro. Interestingly, depletion of TGF-β₃ also attenuates signaling evoked by TGF-β₁ or TGF-β₂. In orthotopic syngeneic (SMA-560) and xenograft (LN-308) in vivo glioma models, expression of TGF-β₃ as well as of the downstream target, plasminogen-activator-inhibitor (PAI)-1, was reduced, while TGF-β₁ and TGF-β₂ levels were unaffected following systemic treatment with TGF-β₃-specific antisense oligonucleotides. We conclude that TGF-β₃ might function as a gatekeeper controlling downstream signaling despite high expression of TGF-β₁ and TGF-β₂ isoforms. Targeting TGF-β₃in vivo may represent a promising strategy interfering with aberrant TGF-β signaling in glioblastoma. Mol Cancer Ther; 16(6); 1177–86. ©2017 AACR.

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Correction: Dedifferentiation of Glioma Cells to Glioma Stem-like Cells By Therapeutic Stress-induced HIF Signaling in the Recurrent GBM Model

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A Fas Ligand (FasL)-Fused Humanized Antibody Against Tumor-Associated Glycoprotein 72 Selectively Exhibits the Cytotoxic Effect Against Oral Cancer Cells with a Low FasL/Fas Ratio

Altered expression of the Fas ligand (FasL)/Fas ratio exhibits a direct impact on the prognosis of cancer patients, and its impairment in cancer cells may lead to apoptosis resistance. Thus, the development of effective therapies targeting the FasL/Fas system may play an important role in the fight against cancer. In this study, we evaluated whether a fusion protein (hcc49scFv-FasL) comprising of the cytotoxicity domain of the FasL fused to a humanized antibody (CC49) against tumor-associated glycoprotein 72, which is expressed on oral squamous cell carcinoma (OSCC), can selectively kill OSCC cells with different FasL/Fas ratios. In clinical samples, the significantly low FasL and high Fas transcripts were observed in tumors compared with normal tissues. A lower FasL/Fas ratio was correlated with a worse prognosis of OSCC patients and higher proliferative and invasive abilities of OSCC cells. The hcc49scFv-FasL showed a selective cytotoxic effect on OSCC cells (Cal-27 and SAS) but not on normal oral keratinocytes cells (HOK) through apoptosis induction. Moreover, SAS cells harboring a lower FasL/Fas ratio than Cal-27 were more sensitive to the cytotoxic effect of hcc49scFv-FasL. Unlike wild-type FasL, hcc49scFv-FasL was not cleaved by matrix metalloproteinases and did not induce nonapoptotic signaling in SAS cells. In vivo, we found that hcc49scFv-FasL drastically reduced the formation of lymph node metastasis and decreased primary tumor growth in SAS orthotopic and subcutaneous xenograft tumor models. Collectively, our data indicate that a tumor-targeting antibody fused to the FasL can be a powerful tool for OSCC treatment, especially in populations with a low FasL/Fas ratio. Mol Cancer Ther; 16(6); 1102–13. ©2017 AACR.

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Optimizing Therapeutic Effect of Aurora B Inhibition in Acute Myeloid Leukemia with AZD2811 Nanoparticles

Barasertib (AZD1152), a highly potent and selective aurora kinase B inhibitor, gave promising clinical activity in elderly acute myeloid leukemia (AML) patients. However, clinical utility was limited by the requirement for a 7-day infusion. Here we assessed the potential of a nanoparticle formulation of the selective Aurora kinase B inhibitor AZD2811 (formerly known as AZD1152-hQPA) in preclinical models of AML. When administered to HL-60 tumor xenografts at a single dose between 25 and 98.7 mg/kg, AZD2811 nanoparticle treatment delivered profound inhibition of tumor growth, exceeding the activity of AZD1152. The improved antitumor activity was associated with increased phospho-histone H3 inhibition, polyploidy, and tumor cell apoptosis. Moreover, AZD2811 nanoparticles increased antitumor activity when combined with cytosine arabinoside. By modifying dose of AZD2811 nanoparticle, therapeutic benefit in a range of preclinical models was further optimized. At high-dose, antitumor activity was seen in a range of models including the MOLM-13 disseminated model. At these higher doses, a transient reduction in bone marrow cellularity was observed demonstrating the potential for the formulation to target residual disease in the bone marrow, a key consideration when treating AML. Collectively, these data establish that AZD2811 nanoparticles have activity in preclinical models of AML. Targeting Aurora B kinase with AZD2811 nanoparticles is a novel approach to deliver a cell-cycle inhibitor in AML, and have potential to improve on the clinical activity seen with cell-cycle agents in this disease. Mol Cancer Ther; 16(6); 1031–40. ©2017 AACR.

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Resistance Mechanism against Trastuzumab in HER2-Positive Cancer Cells and Its Negation by Src Inhibition

Trastuzumab in combination with chemotherapy is the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancers. Several resistance mechanisms against anti-HER2 therapy have been proposed. Src activation has been suggested to be responsible for the resistance of HER2-positive breast cancer. In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from HER2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773). Elevated Src phosphorylation was detected in SNU2670HR and NCI-N87HR cell lines, but not in SNU216HR or SNU2773HR cell lines. In SNU216HR and SNU2773HR cell lines, phospho-FAK (focal adhesion kinase) was elevated. Bosutinib as a Src inhibitor suppressed growth, cell-cycle progression, and migration in both parental and HR cell lines. Specifically, Src interacted with FAK to affect downstream molecules such as AKT, ERK, and STAT3. Bosutinib showed more potent antitumor effects in Src-activated HR cell lines than parental cell lines. Taken together, this study suggests that Src inhibition may be an effective measure to overcome trastuzumab resistance in HER2-positive cancer. Mol Cancer Ther; 16(6); 1145–54. ©2017 AACR.

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Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor

Pancreatic adenocarcinoma (PDAC) is the fourth most common cause of cancer-related death in the United States. PDAC is difficult to manage effectively, with a five-year survival rate of only 5%. PDAC is largely driven by activating KRAS mutations, and as such, cannot be directly targeted with therapeutic agents that affect the activated protein. Instead, inhibition of downstream signaling and other targets will be necessary to effectively manage PDAC. Here, we describe a tiered single-agent and combination compound screen to identify targeted agents that impair growth of a panel of PDAC cell lines. Several of the combinations identified from the screen were further validated for efficacy and mechanism. Combination of the bromodomain inhibitor JQ1 and the neddylation inhibitor MLN4294 altered the production of reactive oxygen species in PDAC cells, ultimately leading to defects in the DNA damage response. Dual bromodomain/neddylation blockade inhibited in vivo growth of PDAC cell line xenografts. Overall, this work revealed novel combinatorial regimens, including JQ1 plus MLN4294, which show promise for the treatment of RAS-driven PDAC. Mol Cancer Ther; 16(6); 1041–53. ©2017 AACR.

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Maltotriose Conjugation to a Chlorin Derivative Enhances the Antitumor Effects of Photodynamic Therapy in Peritoneal Dissemination of Pancreatic Cancer

Peritoneal dissemination is a major clinical issue associated with dismal prognosis and poor quality of life for patients with pancreatic cancer; however, no effective treatment strategies have been established. Herein, we evaluated the effects of photodynamic therapy (PDT) with maltotriose-conjugated chlorin (Mal₃-chlorin) in culture and in a peritoneal disseminated mice model of pancreatic cancer. The Mal₃-chlorin was prepared as a water-soluble chlorin derivative conjugated with four Mal₃ molecules to improve cancer selectivity. In vitro, Mal₃-chlorin showed superior uptake into pancreatic cancer cells compared with talaporfin, which is clinically used. Moreover, the strong cytotoxic effects of PDT with Mal₃-chlorin occurred via apoptosis and reactive oxygen species generation, whereas Mal₃-chlorin alone did not cause any cytotoxicity in pancreatic cancer cells. Notably, using a peritoneal disseminated mice model, we demonstrated that Mal₃-chlorin accumulated in xenograft tumors and suppressed both tumor growth and ascites formation with PDT. Furthermore, PDT with Mal₃-chlorin induced robust apoptosis in peritoneal disseminated tumors, as indicated by immunohistochemistry. Taken together, these findings implicate Mal₃-chlorin as a potential next-generation photosensitizer for PDT and the basis of a new strategy for managing peritoneal dissemination of pancreatic cancer. Mol Cancer Ther; 16(6); 1124–32. ©2017 AACR.

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Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics

Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348, we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from patients with myeloproliferative neoplasm. Screening across 931 cancer cell lines revealed differential growth inhibitory potential with highest activity against bone and blood cancers and greatly enhanced activity over the single BET inhibitor JQ1. Gene drug sensitivity analyses and drug combination studies indicate synergism of BRD4 and kinase inhibition as a plausible reason for the superior potency in cell killing. Combined, our findings indicate promising potential of these agents as novel chemical probes and cancer therapeutics. Mol Cancer Ther; 16(6); 1054–67. ©2017 AACR.

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Disruption of TCF/{beta}-Catenin Binding Impairs Wnt Signaling and Induces Apoptosis in Soft Tissue Sarcoma Cells

Soft tissue sarcomas (STS) are malignant tumors of mesenchymal origin and represent around 1% of adult cancers, being a very heterogeneous group of tumors with more than 50 different subtypes. The Wnt signaling pathway is involved in the development and in the regulation, self-renewal, and differentiation of mesenchymal stem cells, and plays a role in sarcomagenesis. In this study, we have tested pharmacologic inhibition of Wnt signaling mediated by disruption of TCF/β-catenin binding and AXIN stabilization, being the first strategy more efficient in reducing cell viability and downstream effects. We have shown that disruption of TCF/β-catenin binding with PKF118-310 produces in vitro antitumor activity in a panel of prevalent representative STS cell lines and primary cultures. At the molecular level, PKF118-310 treatment reduced β-catenin nuclear localization, reporter activity, and target genes, resulting in an increase in apoptosis. Importantly, combination of PKF118-310 with doxorubicin resulted in enhanced reduction of cell viability, suggesting that Wnt inhibition could be a new combination regime in these patients. Our findings support the usefulness of Wnt inhibitors as new therapeutic strategies for the prevalent STS. Mol Cancer Ther; 16(6); 1166–76. ©2017 AACR.

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The TLR3 Agonist Inhibit Drug Efflux and Sequentially Consolidates Low-Dose Cisplatin-Based Chemoimmunotherapy while Reducing Side Effects

The traditional maximum dose density chemotherapy renders the tumor patients not only the tumor remission but the chemotherapy resistance and more adverse side effects. According to the widely positive expression of Toll-like receptor (TLR)-3 in oral squamous cell carcinoma (OSCC) patients (n = 166), we here provided an alternative strategy involved the orderly treatment of TLR3 agonist polyinosine–polycytidylic acid (PIC) and low-dose cisplatin. The optimal dose of cisplatin, the novel role of PIC and the side effects of the combined chemotherapy were determined in vitro and in distinct human tumor models in vivo. The results in vitro indicated that preculture with PIC downregulated drug transporters (e.g., P-gp and MRP-1) and increased the cytoplasmic residence of cisplatin, and dramatically strengthened the low-dose cisplatin-induced cell death in TLR3- and caspase-3–dependent manner. Meanwhile, the spleen immunocytes were activated but the immunosuppressive cancer-associated fibroblasts (CAF) were dampened. These findings were confirmed in human tumor models in vivo. Pretreatment with PIC promoted the low-dose cisplatin residence for tumor regression with decreased myeloid-suppressive cells (MDSC), tumor-associated macrophages (TAM) and CAFs, and alleviated adverse side effects in the OSCC model, which was further enhanced by the Cetuximab safely. This strategy also repressed the progression of melanoma and lymphoma. Moreover, TLR3 negatively manipulated the inflammation-related long noncoding RNA lnc-IL7R, which was upregulated during this chemotherapy. Knockdown of lnc-IL7R improved the chemotherapy sensitivity. Overall, this study provided preclinically new instructions for the PIC/cisplatin utilization to target tumor microenvironment and strengthen the low-dose cisplatin-based chemotherapy with reduced side effects. Mol Cancer Ther; 16(6); 1068–79. ©2017 AACR.

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Preclinical Mammalian Safety Studies of EPHARNA (DOPC Nanoliposomal EphA2-Targeted siRNA)

To address the need for efficient and biocompatible delivery systems for systemic siRNA delivery, we developed 1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine (DOPC) nanoliposomal EphA2-targeted therapeutic (EPHARNA). Here, we performed safety studies of EPHARNA in murine and primate models. Single dosing of EPHARNA was tested at 5 concentrations in mice (N = 15 per group) and groups were sacrificed on days 1, 14, and 28 for evaluation of clinical pathology and organ toxicity. Multiple dosing of EPHARNA was tested in mice and Rhesus macaques twice weekly at two dose levels in each model. Possible effects on hematologic parameters, serum chemistry, coagulation, and organ toxicity were assessed. Following single-dose EPHARNA administration to mice, no gross pathologic or dose-related microscopic findings were observed in either the acute (24 hours) or recovery (14 and 28 days) phases. The no-observed-adverse-effect level (NOAEL) for EPHARNA is considered >225 μg/kg when administered as a single injection intravenously in CD-1 mice. With twice weekly injection, EPHARNA appeared to stimulate a mild to moderate inflammatory response in a dose-related fashion. There appeared to be a mild hemolytic reaction in the female mice. In Rhesus macaques, minimal to moderate infiltration of mononuclear cells was found in some organs including the gastrointestinal tract, heart, and kidney. No differences attributed to EPHARNA were observed. These results demonstrate that EPHARNA is well tolerated at all doses tested. These data, combined with previously published in vivo validation studies, have led to an ongoing first-in-human phase I clinical trial (NCT01591356). Mol Cancer Ther; 16(6); 1114–23. ©2017 AACR.

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Acquired Resistance with Epigenetic Alterations Under Long-Term Antiangiogenic Therapy for Hepatocellular Carcinoma

Antiangiogenic therapy is initially effective for several solid tumors including hepatocellular carcinoma; however, they finally relapse and progress, resulting in poor prognosis. We here established in vivo drug-tolerant subclones of human hepatocellular carcinoma cells by long-term treatment with VEGF receptor (VEGFR) inhibitor and serial transplantation in immunocompromised mice (total 12 months), and then compared them with the parental cells in molecular and biological features. Gene expression profiles elucidated a G-actin monomer binding protein thymosin β 4 (Tβ4) as one of the genes enriched in the resistant cancer cells relative to the initially sensitive ones. Highlighting epigenetic alterations involved in drug resistance, we revealed that Tβ4 could be aberrantly expressed following demethylation of DNA and active modification of histone H3 at the promoter region. Ectopic overexpression of Tβ4 in hepatocellular carcinoma cells could significantly enhance sphere-forming capacities and infiltrating phenotypes in vitro, and promote growth of tumors refractory to the VEGFR multikinase inhibitor sorafenib in vivo. Clinically, sorafenib failed to improve the progression-free survival in patients with Tβ4-high hepatocellular carcinoma, indicating that Tβ4 expression could be available as a surrogate marker of susceptibility to this drug. This study suggests that Tβ4 expression triggered by epigenetic alterations could contribute to the development of resistance to antiangiogenic therapy by the acquisition of stemness, and that epigenetic control might be one of the key targets to regulate the resistance in hepatocellular carcinoma. Mol Cancer Ther; 16(6); 1155–65. ©2017 AACR.

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Focal Adhesion Kinase as a Potential Target in AML and MDS

Although overexpression/activation of focal adhesion kinase (FAK) is widely known in solid tumors to control cell growth, survival, invasion, metastasis, gene expression, and stem cell self-renewal, its expression and function in myeloid leukemia are not well investigated. Using reverse-phase protein arrays in large cohorts of newly diagnosed acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS) samples, we found that high FAK expression was associated with unfavorable cytogenetics (P = 2 x 10^–4) and relapse (P = 0.02) in AML. FAK expression was significantly lower in patients with FLT3-ITD (P = 0.0024) or RAS (P = 0.05) mutations and strongly correlated with p-SRC and integrinβ3 levels. FAK protein levels were significantly higher in CD34⁺ (P = 5.42 x 10^–20) and CD34⁺CD38^– MDS (P = 7.62 x 10^–9) cells compared with normal CD34⁺ cells. MDS patients with higher FAK in CD34⁺ cells tended to have better overall survival (P = 0.05). FAK expression was significantly higher in MDS patients who later transformed to compared with those who did not transform to AML and in AML patients who transformed from MDS compared with those with de novo AML. Coculture with mesenchymal stromal cells (MSC) increased FAK expression in AML cells. Inhibition of FAK decreased MSC-mediated adhesion/migration and viability of AML cells and prolonged survival in an AML xenograft murine model. Our results suggest that FAK regulates leukemia–stromal interactions and supports leukemia cell survival; hence, FAK is a potential therapeutic target in myeloid leukemia. Mol Cancer Ther; 16(6); 1133–44. ©2017 AACR.

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The Slow Cycling Phenotype: A Growing Problem for Treatment Resistance in Melanoma

Treatment resistance in metastatic melanoma is a longstanding issue. Current targeted therapy regimes in melanoma largely target the proliferating cancer population, leaving slow-cycling cancer cells undamaged. Consequently, slow-cycling cells are enriched upon drug therapy and can remain in the body for years until acquiring proliferative potential that triggers cancer relapse. Here we overview the molecular mechanisms of slow-cycling cells that underlie treatment resistance in melanoma. Three main areas of molecular reprogramming are discussed that mediate slow cycling and treatment resistance. First, a low microphthalmia-associated transcription factor (MITF) dedifferentiated state activates various signaling pathways. This includes WNT5A, EGFR, as well as other signaling activators, such as AXL and NF-B. Second, the chromatin-remodeling factor Jumonji/ARID domain-containing protein 1B (JARID1B, KDM5B) orchestrates and maintains slow cycling and treatment resistance in a small subpopulation of melanoma cells. Finally, a shift in metabolic state toward oxidative phosphorylation has been demonstrated to regulate treatment resistance in slow-cycling cells. Elucidation of the underlying processes of slow cycling and its utilization by melanoma cells may reveal new vulnerable characteristics as therapeutic targets. Moreover, combining current therapies with targeting slow-cycling subpopulations of melanoma cells may allow for more durable and greater treatment responses. Mol Cancer Ther; 16(6); 1002–9. ©2017 AACR.

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The BTK Inhibitor Ibrutinib (PCI-32765) Overcomes Paclitaxel Resistance in ABCB1- and ABCC10-Overexpressing Cells and Tumors

Paclitaxel is one of the most widely used antineoplastic drugs in the clinic. Unfortunately, the occurrence of cellular resistance has limited its efficacy and application. The ATP-binding cassette subfamily B member 1 (ABCB1/P-glycoprotein) and subfamily C member 10 (ABCC10/MRP7) are the major membrane protein transporters responsible for the efflux of paclitaxel, constituting one of the most important mechanisms of paclitaxel resistance. Here, we demonstrated that the Bruton tyrosine kinase inhibitor, ibrutinib, significantly enhanced the antitumor activity of paclitaxel by antagonizing the efflux function of ABCB1 and ABCC10 in cells overexpressing these transporters. Furthermore, we demonstrated that the ABCB1 or ABCC10 protein expression was not altered after treatment with ibrutinib for up to 72 hours using Western blot analysis. However, the ATPase activity of ABCB1 was significantly stimulated by treatment with ibrutinib. Molecular docking analysis suggested the binding conformation of ibrutinib within the large cavity of the transmembrane region of ABCB1. Importantly, ibrutinib could effectively enhance paclitaxel-induced inhibition on the growth of ABCB1- and ABCC10-overexpressing tumors in nude athymic mice. These results demonstrate that the combination of ibrutinib and paclitaxel can effectively antagonize ABCB1- or ABCC10-mediated paclitaxel resistance that could be of great clinical interest. Mol Cancer Ther; 16(6); 1021–30. ©2017 AACR.

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Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor

Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases. JNJ-42756493 shows rapid uptake into the lysosomal compartment of cells in culture, which is associated with prolonged inhibition of FGFR signaling, possibly due to sustained release of the inhibitor. In xenografts from human tumor cell lines or patient-derived tumor tissue with activating FGFR alterations, JNJ-42756493 administration results in potent and dose-dependent antitumor activity accompanied by pharmacodynamic modulation of phospho-FGFR and phospho-ERK in tumors. The results of the current study provide a strong rationale for the clinical investigation of JNJ-42756493 in patients with tumors harboring FGFR pathway alterations. Mol Cancer Ther; 16(6); 1010–20. ©2017 AACR.

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Highlights of This Issue

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G-1 Inhibits Breast Cancer Cell Growth via Targeting Colchicine-Binding Site of Tubulin to Interfere with Microtubule Assembly

G-protein–coupled estrogen receptor 1 (GPER1) has been reported to play a significant role in mediating the rapid estrogen actions in a wide range of normal and cancer cells. G-1 was initially developed as a selective agonist for GPER. However, the molecular mechanisms underlying the actions of G-1 are unknown, and recent studies report inconsistent effects of G-1 on the growth of breast cancer cells. By employing high-resolution laser scanning confocal microscopy and time-lapse imaging technology, as well as biochemical analyses, in the current study, we provide convincing in vitro and in vivo evidence that G-1 is able to suppress the growth of breast cancer cells independent of the expression status of GPERs and classic estrogen receptors. Interestingly, we found that triple-negative breast cancer cells (TNBC) are very sensitive to G-1 treatment. We found that G-1 arrested the cell cycle in the prophase of mitosis, leading to caspase activation and apoptosis of breast cancer cells. Our mechanistic studies indicated that G-1, similar to colchicine and 2-methoxyestradiol, binds to colchicine binding site on tubulin, inhibiting tubulin polymerization and subsequent assembly of normal mitotic spindle apparatus during breast cancer cell mitosis. Therefore, G-1 is a novel microtubule-targeting agent and could be a promising anti-microtubule drug for breast cancer treatment, especially for TNBC treatment. Mol Cancer Ther; 16(6); 1080–91. ©2017 AACR.

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Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53-Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death

Photodynamic therapy (PDT), using 5-aminolevulinic acid (ALA) to drive synthesis of protoporphryin IX (PpIX) is a promising, scar-free alternative to surgery for skin cancers, including squamous cell carcinoma (SCC) and SCC precursors called actinic keratoses. In the United States, PDT is only FDA approved for treatment of actinic keratoses; this narrow range of indications could be broadened if PDT efficacy were improved. Toward that goal, we developed a mechanism-based combination approach using 5-fluorouracil (5-FU) as a neoadjuvant for ALA-based PDT. In mouse models of SCC (orthotopic UV-induced lesions, and subcutaneous A431 and 4T1 tumors), pretreatment with 5-FU for 3 days followed by ALA for 4 hours led to large, tumor-selective increases in PpIX levels, and enhanced cell death upon illumination. Several mechanisms were identified that might explain the relatively improved therapeutic response. First, the expression of key enzymes in the heme synthesis pathway was altered, including upregulated coproporphyrinogen oxidase and downregulated ferrochelatase. Second, a 3- to 6-fold induction of p53 in 5-FU–pretreated tumors was noted. The fact that A431 contains a mutant form p53 did not prevent the development of a neoadjuvantal 5-FU effect. Furthermore, 5-FU pretreatment of 4T1 tumors (cells that completely lack p53), still led to significant beneficial inductions, that is, 2.5-fold for both PpIX and PDT-induced cell death. Thus, neoadjuvantal 5-FU combined with PDT represents a new therapeutic approach that appears useful even for p53-mutant and p53-null tumors. Mol Cancer Ther; 16(6); 1092–101. ©2017 AACR.

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PMP22 Regulates Self-Renewal and Chemoresistance of Gastric Cancer Cells

Cancer stem cells possess self-renewal and chemoresistance activities. However, the manner in which these features are maintained remains obscure. We sought to identify cell surface protein(s) that mark self-renewing and chemoresistant gastric cancer cells using the explorer antibody microarray. We identified PMP22, a target gene of the Wnt/β-catenin pathway, as the most upregulated cell surface protein in gastric cancer xenografts exposed to cisplatin (DDP). PMP22 expression was markedly upregulated in tumorspheric cells and declined with differentiation. Infecting gastric cancer cells with lentivirus expressing PMP22 shRNAs reduced proliferation, tumorsphere formation, and chemoresistance to cisplatin in vitro and in NOD/SCID mice. When combined with bortezomib, a PMP22 inhibitor, the chemotherapeutic sensitivity to cisplatin treatment was dramatically increased by inducing cell apoptosis in cultured cells and xenograft mouse models. Finally, mRNA expression levels of PMP22 were detected in 38 tumor specimens from patients who received six cycles of perioperative chemotherapy. A strong correlation between PMP22 level and tumor recurrence was revealed, thus showing a pivotal role of PMP22 in the clinical chemoresistance of gastric cancer. Our study is the first to show the role of PMP22 in gastric cancer stemness and chemoresistance and reveals a potential new target for the diagnosis and treatment of recurrent gastric cancer. Mol Cancer Ther; 16(6); 1187–98. ©2017 AACR.

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Biological Role and Therapeutic Targeting of TGF-{beta}3 in Glioblastoma

Transforming growth factor (TGF)-β contributes to the malignant phenotype of glioblastoma by promoting invasiveness and angiogenesis and creating an immunosuppressive microenvironment. So far, TGF-β₁ and TGF-β₂ isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma. A pathogenic role for TGF-β₃ in glioblastoma has not been defined yet. Here, we studied the expression and functional role of endogenous and exogenous TGF-β₃ in glioblastoma models. TGF-β₃ mRNA is expressed in human and murine long-term glioma cell lines as well as in human glioma-initiating cell cultures with expression levels lower than TGF-β₁ or TGF-β₂ in most cell lines. Inhibition of TGF-β₃ mRNA expression by ISTH2020 or ISTH2023, two different isoform-specific phosphorothioate locked nucleic acid (LNA)-modified antisense oligonucleotide gapmers, blocks downstream SMAD2 and SMAD1/5 phosphorylation in human LN-308 cells, without affecting TGF-β₁ or TGF-β₂ mRNA expression or protein levels. Moreover, inhibition of TGF-β₃ expression reduces invasiveness in vitro. Interestingly, depletion of TGF-β₃ also attenuates signaling evoked by TGF-β₁ or TGF-β₂. In orthotopic syngeneic (SMA-560) and xenograft (LN-308) in vivo glioma models, expression of TGF-β₃ as well as of the downstream target, plasminogen-activator-inhibitor (PAI)-1, was reduced, while TGF-β₁ and TGF-β₂ levels were unaffected following systemic treatment with TGF-β₃-specific antisense oligonucleotides. We conclude that TGF-β₃ might function as a gatekeeper controlling downstream signaling despite high expression of TGF-β₁ and TGF-β₂ isoforms. Targeting TGF-β₃in vivo may represent a promising strategy interfering with aberrant TGF-β signaling in glioblastoma. Mol Cancer Ther; 16(6); 1177–86. ©2017 AACR.

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Correction: Dedifferentiation of Glioma Cells to Glioma Stem-like Cells By Therapeutic Stress-induced HIF Signaling in the Recurrent GBM Model

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A Fas Ligand (FasL)-Fused Humanized Antibody Against Tumor-Associated Glycoprotein 72 Selectively Exhibits the Cytotoxic Effect Against Oral Cancer Cells with a Low FasL/Fas Ratio

Altered expression of the Fas ligand (FasL)/Fas ratio exhibits a direct impact on the prognosis of cancer patients, and its impairment in cancer cells may lead to apoptosis resistance. Thus, the development of effective therapies targeting the FasL/Fas system may play an important role in the fight against cancer. In this study, we evaluated whether a fusion protein (hcc49scFv-FasL) comprising of the cytotoxicity domain of the FasL fused to a humanized antibody (CC49) against tumor-associated glycoprotein 72, which is expressed on oral squamous cell carcinoma (OSCC), can selectively kill OSCC cells with different FasL/Fas ratios. In clinical samples, the significantly low FasL and high Fas transcripts were observed in tumors compared with normal tissues. A lower FasL/Fas ratio was correlated with a worse prognosis of OSCC patients and higher proliferative and invasive abilities of OSCC cells. The hcc49scFv-FasL showed a selective cytotoxic effect on OSCC cells (Cal-27 and SAS) but not on normal oral keratinocytes cells (HOK) through apoptosis induction. Moreover, SAS cells harboring a lower FasL/Fas ratio than Cal-27 were more sensitive to the cytotoxic effect of hcc49scFv-FasL. Unlike wild-type FasL, hcc49scFv-FasL was not cleaved by matrix metalloproteinases and did not induce nonapoptotic signaling in SAS cells. In vivo, we found that hcc49scFv-FasL drastically reduced the formation of lymph node metastasis and decreased primary tumor growth in SAS orthotopic and subcutaneous xenograft tumor models. Collectively, our data indicate that a tumor-targeting antibody fused to the FasL can be a powerful tool for OSCC treatment, especially in populations with a low FasL/Fas ratio. Mol Cancer Ther; 16(6); 1102–13. ©2017 AACR.

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Optimizing Therapeutic Effect of Aurora B Inhibition in Acute Myeloid Leukemia with AZD2811 Nanoparticles

Barasertib (AZD1152), a highly potent and selective aurora kinase B inhibitor, gave promising clinical activity in elderly acute myeloid leukemia (AML) patients. However, clinical utility was limited by the requirement for a 7-day infusion. Here we assessed the potential of a nanoparticle formulation of the selective Aurora kinase B inhibitor AZD2811 (formerly known as AZD1152-hQPA) in preclinical models of AML. When administered to HL-60 tumor xenografts at a single dose between 25 and 98.7 mg/kg, AZD2811 nanoparticle treatment delivered profound inhibition of tumor growth, exceeding the activity of AZD1152. The improved antitumor activity was associated with increased phospho-histone H3 inhibition, polyploidy, and tumor cell apoptosis. Moreover, AZD2811 nanoparticles increased antitumor activity when combined with cytosine arabinoside. By modifying dose of AZD2811 nanoparticle, therapeutic benefit in a range of preclinical models was further optimized. At high-dose, antitumor activity was seen in a range of models including the MOLM-13 disseminated model. At these higher doses, a transient reduction in bone marrow cellularity was observed demonstrating the potential for the formulation to target residual disease in the bone marrow, a key consideration when treating AML. Collectively, these data establish that AZD2811 nanoparticles have activity in preclinical models of AML. Targeting Aurora B kinase with AZD2811 nanoparticles is a novel approach to deliver a cell-cycle inhibitor in AML, and have potential to improve on the clinical activity seen with cell-cycle agents in this disease. Mol Cancer Ther; 16(6); 1031–40. ©2017 AACR.

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Resistance Mechanism against Trastuzumab in HER2-Positive Cancer Cells and Its Negation by Src Inhibition

Trastuzumab in combination with chemotherapy is the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancers. Several resistance mechanisms against anti-HER2 therapy have been proposed. Src activation has been suggested to be responsible for the resistance of HER2-positive breast cancer. In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from HER2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773). Elevated Src phosphorylation was detected in SNU2670HR and NCI-N87HR cell lines, but not in SNU216HR or SNU2773HR cell lines. In SNU216HR and SNU2773HR cell lines, phospho-FAK (focal adhesion kinase) was elevated. Bosutinib as a Src inhibitor suppressed growth, cell-cycle progression, and migration in both parental and HR cell lines. Specifically, Src interacted with FAK to affect downstream molecules such as AKT, ERK, and STAT3. Bosutinib showed more potent antitumor effects in Src-activated HR cell lines than parental cell lines. Taken together, this study suggests that Src inhibition may be an effective measure to overcome trastuzumab resistance in HER2-positive cancer. Mol Cancer Ther; 16(6); 1145–54. ©2017 AACR.

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Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor

Pancreatic adenocarcinoma (PDAC) is the fourth most common cause of cancer-related death in the United States. PDAC is difficult to manage effectively, with a five-year survival rate of only 5%. PDAC is largely driven by activating KRAS mutations, and as such, cannot be directly targeted with therapeutic agents that affect the activated protein. Instead, inhibition of downstream signaling and other targets will be necessary to effectively manage PDAC. Here, we describe a tiered single-agent and combination compound screen to identify targeted agents that impair growth of a panel of PDAC cell lines. Several of the combinations identified from the screen were further validated for efficacy and mechanism. Combination of the bromodomain inhibitor JQ1 and the neddylation inhibitor MLN4294 altered the production of reactive oxygen species in PDAC cells, ultimately leading to defects in the DNA damage response. Dual bromodomain/neddylation blockade inhibited in vivo growth of PDAC cell line xenografts. Overall, this work revealed novel combinatorial regimens, including JQ1 plus MLN4294, which show promise for the treatment of RAS-driven PDAC. Mol Cancer Ther; 16(6); 1041–53. ©2017 AACR.

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Maltotriose Conjugation to a Chlorin Derivative Enhances the Antitumor Effects of Photodynamic Therapy in Peritoneal Dissemination of Pancreatic Cancer

Peritoneal dissemination is a major clinical issue associated with dismal prognosis and poor quality of life for patients with pancreatic cancer; however, no effective treatment strategies have been established. Herein, we evaluated the effects of photodynamic therapy (PDT) with maltotriose-conjugated chlorin (Mal₃-chlorin) in culture and in a peritoneal disseminated mice model of pancreatic cancer. The Mal₃-chlorin was prepared as a water-soluble chlorin derivative conjugated with four Mal₃ molecules to improve cancer selectivity. In vitro, Mal₃-chlorin showed superior uptake into pancreatic cancer cells compared with talaporfin, which is clinically used. Moreover, the strong cytotoxic effects of PDT with Mal₃-chlorin occurred via apoptosis and reactive oxygen species generation, whereas Mal₃-chlorin alone did not cause any cytotoxicity in pancreatic cancer cells. Notably, using a peritoneal disseminated mice model, we demonstrated that Mal₃-chlorin accumulated in xenograft tumors and suppressed both tumor growth and ascites formation with PDT. Furthermore, PDT with Mal₃-chlorin induced robust apoptosis in peritoneal disseminated tumors, as indicated by immunohistochemistry. Taken together, these findings implicate Mal₃-chlorin as a potential next-generation photosensitizer for PDT and the basis of a new strategy for managing peritoneal dissemination of pancreatic cancer. Mol Cancer Ther; 16(6); 1124–32. ©2017 AACR.

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Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics

Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348, we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from patients with myeloproliferative neoplasm. Screening across 931 cancer cell lines revealed differential growth inhibitory potential with highest activity against bone and blood cancers and greatly enhanced activity over the single BET inhibitor JQ1. Gene drug sensitivity analyses and drug combination studies indicate synergism of BRD4 and kinase inhibition as a plausible reason for the superior potency in cell killing. Combined, our findings indicate promising potential of these agents as novel chemical probes and cancer therapeutics. Mol Cancer Ther; 16(6); 1054–67. ©2017 AACR.

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Disruption of TCF/{beta}-Catenin Binding Impairs Wnt Signaling and Induces Apoptosis in Soft Tissue Sarcoma Cells

Soft tissue sarcomas (STS) are malignant tumors of mesenchymal origin and represent around 1% of adult cancers, being a very heterogeneous group of tumors with more than 50 different subtypes. The Wnt signaling pathway is involved in the development and in the regulation, self-renewal, and differentiation of mesenchymal stem cells, and plays a role in sarcomagenesis. In this study, we have tested pharmacologic inhibition of Wnt signaling mediated by disruption of TCF/β-catenin binding and AXIN stabilization, being the first strategy more efficient in reducing cell viability and downstream effects. We have shown that disruption of TCF/β-catenin binding with PKF118-310 produces in vitro antitumor activity in a panel of prevalent representative STS cell lines and primary cultures. At the molecular level, PKF118-310 treatment reduced β-catenin nuclear localization, reporter activity, and target genes, resulting in an increase in apoptosis. Importantly, combination of PKF118-310 with doxorubicin resulted in enhanced reduction of cell viability, suggesting that Wnt inhibition could be a new combination regime in these patients. Our findings support the usefulness of Wnt inhibitors as new therapeutic strategies for the prevalent STS. Mol Cancer Ther; 16(6); 1166–76. ©2017 AACR.

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The TLR3 Agonist Inhibit Drug Efflux and Sequentially Consolidates Low-Dose Cisplatin-Based Chemoimmunotherapy while Reducing Side Effects

The traditional maximum dose density chemotherapy renders the tumor patients not only the tumor remission but the chemotherapy resistance and more adverse side effects. According to the widely positive expression of Toll-like receptor (TLR)-3 in oral squamous cell carcinoma (OSCC) patients (n = 166), we here provided an alternative strategy involved the orderly treatment of TLR3 agonist polyinosine–polycytidylic acid (PIC) and low-dose cisplatin. The optimal dose of cisplatin, the novel role of PIC and the side effects of the combined chemotherapy were determined in vitro and in distinct human tumor models in vivo. The results in vitro indicated that preculture with PIC downregulated drug transporters (e.g., P-gp and MRP-1) and increased the cytoplasmic residence of cisplatin, and dramatically strengthened the low-dose cisplatin-induced cell death in TLR3- and caspase-3–dependent manner. Meanwhile, the spleen immunocytes were activated but the immunosuppressive cancer-associated fibroblasts (CAF) were dampened. These findings were confirmed in human tumor models in vivo. Pretreatment with PIC promoted the low-dose cisplatin residence for tumor regression with decreased myeloid-suppressive cells (MDSC), tumor-associated macrophages (TAM) and CAFs, and alleviated adverse side effects in the OSCC model, which was further enhanced by the Cetuximab safely. This strategy also repressed the progression of melanoma and lymphoma. Moreover, TLR3 negatively manipulated the inflammation-related long noncoding RNA lnc-IL7R, which was upregulated during this chemotherapy. Knockdown of lnc-IL7R improved the chemotherapy sensitivity. Overall, this study provided preclinically new instructions for the PIC/cisplatin utilization to target tumor microenvironment and strengthen the low-dose cisplatin-based chemotherapy with reduced side effects. Mol Cancer Ther; 16(6); 1068–79. ©2017 AACR.

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Preclinical Mammalian Safety Studies of EPHARNA (DOPC Nanoliposomal EphA2-Targeted siRNA)

To address the need for efficient and biocompatible delivery systems for systemic siRNA delivery, we developed 1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine (DOPC) nanoliposomal EphA2-targeted therapeutic (EPHARNA). Here, we performed safety studies of EPHARNA in murine and primate models. Single dosing of EPHARNA was tested at 5 concentrations in mice (N = 15 per group) and groups were sacrificed on days 1, 14, and 28 for evaluation of clinical pathology and organ toxicity. Multiple dosing of EPHARNA was tested in mice and Rhesus macaques twice weekly at two dose levels in each model. Possible effects on hematologic parameters, serum chemistry, coagulation, and organ toxicity were assessed. Following single-dose EPHARNA administration to mice, no gross pathologic or dose-related microscopic findings were observed in either the acute (24 hours) or recovery (14 and 28 days) phases. The no-observed-adverse-effect level (NOAEL) for EPHARNA is considered >225 μg/kg when administered as a single injection intravenously in CD-1 mice. With twice weekly injection, EPHARNA appeared to stimulate a mild to moderate inflammatory response in a dose-related fashion. There appeared to be a mild hemolytic reaction in the female mice. In Rhesus macaques, minimal to moderate infiltration of mononuclear cells was found in some organs including the gastrointestinal tract, heart, and kidney. No differences attributed to EPHARNA were observed. These results demonstrate that EPHARNA is well tolerated at all doses tested. These data, combined with previously published in vivo validation studies, have led to an ongoing first-in-human phase I clinical trial (NCT01591356). Mol Cancer Ther; 16(6); 1114–23. ©2017 AACR.

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Acquired Resistance with Epigenetic Alterations Under Long-Term Antiangiogenic Therapy for Hepatocellular Carcinoma

Antiangiogenic therapy is initially effective for several solid tumors including hepatocellular carcinoma; however, they finally relapse and progress, resulting in poor prognosis. We here established in vivo drug-tolerant subclones of human hepatocellular carcinoma cells by long-term treatment with VEGF receptor (VEGFR) inhibitor and serial transplantation in immunocompromised mice (total 12 months), and then compared them with the parental cells in molecular and biological features. Gene expression profiles elucidated a G-actin monomer binding protein thymosin β 4 (Tβ4) as one of the genes enriched in the resistant cancer cells relative to the initially sensitive ones. Highlighting epigenetic alterations involved in drug resistance, we revealed that Tβ4 could be aberrantly expressed following demethylation of DNA and active modification of histone H3 at the promoter region. Ectopic overexpression of Tβ4 in hepatocellular carcinoma cells could significantly enhance sphere-forming capacities and infiltrating phenotypes in vitro, and promote growth of tumors refractory to the VEGFR multikinase inhibitor sorafenib in vivo. Clinically, sorafenib failed to improve the progression-free survival in patients with Tβ4-high hepatocellular carcinoma, indicating that Tβ4 expression could be available as a surrogate marker of susceptibility to this drug. This study suggests that Tβ4 expression triggered by epigenetic alterations could contribute to the development of resistance to antiangiogenic therapy by the acquisition of stemness, and that epigenetic control might be one of the key targets to regulate the resistance in hepatocellular carcinoma. Mol Cancer Ther; 16(6); 1155–65. ©2017 AACR.

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Focal Adhesion Kinase as a Potential Target in AML and MDS

Although overexpression/activation of focal adhesion kinase (FAK) is widely known in solid tumors to control cell growth, survival, invasion, metastasis, gene expression, and stem cell self-renewal, its expression and function in myeloid leukemia are not well investigated. Using reverse-phase protein arrays in large cohorts of newly diagnosed acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS) samples, we found that high FAK expression was associated with unfavorable cytogenetics (P = 2 x 10^–4) and relapse (P = 0.02) in AML. FAK expression was significantly lower in patients with FLT3-ITD (P = 0.0024) or RAS (P = 0.05) mutations and strongly correlated with p-SRC and integrinβ3 levels. FAK protein levels were significantly higher in CD34⁺ (P = 5.42 x 10^–20) and CD34⁺CD38^– MDS (P = 7.62 x 10^–9) cells compared with normal CD34⁺ cells. MDS patients with higher FAK in CD34⁺ cells tended to have better overall survival (P = 0.05). FAK expression was significantly higher in MDS patients who later transformed to compared with those who did not transform to AML and in AML patients who transformed from MDS compared with those with de novo AML. Coculture with mesenchymal stromal cells (MSC) increased FAK expression in AML cells. Inhibition of FAK decreased MSC-mediated adhesion/migration and viability of AML cells and prolonged survival in an AML xenograft murine model. Our results suggest that FAK regulates leukemia–stromal interactions and supports leukemia cell survival; hence, FAK is a potential therapeutic target in myeloid leukemia. Mol Cancer Ther; 16(6); 1133–44. ©2017 AACR.

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The Slow Cycling Phenotype: A Growing Problem for Treatment Resistance in Melanoma

Treatment resistance in metastatic melanoma is a longstanding issue. Current targeted therapy regimes in melanoma largely target the proliferating cancer population, leaving slow-cycling cancer cells undamaged. Consequently, slow-cycling cells are enriched upon drug therapy and can remain in the body for years until acquiring proliferative potential that triggers cancer relapse. Here we overview the molecular mechanisms of slow-cycling cells that underlie treatment resistance in melanoma. Three main areas of molecular reprogramming are discussed that mediate slow cycling and treatment resistance. First, a low microphthalmia-associated transcription factor (MITF) dedifferentiated state activates various signaling pathways. This includes WNT5A, EGFR, as well as other signaling activators, such as AXL and NF-B. Second, the chromatin-remodeling factor Jumonji/ARID domain-containing protein 1B (JARID1B, KDM5B) orchestrates and maintains slow cycling and treatment resistance in a small subpopulation of melanoma cells. Finally, a shift in metabolic state toward oxidative phosphorylation has been demonstrated to regulate treatment resistance in slow-cycling cells. Elucidation of the underlying processes of slow cycling and its utilization by melanoma cells may reveal new vulnerable characteristics as therapeutic targets. Moreover, combining current therapies with targeting slow-cycling subpopulations of melanoma cells may allow for more durable and greater treatment responses. Mol Cancer Ther; 16(6); 1002–9. ©2017 AACR.

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The BTK Inhibitor Ibrutinib (PCI-32765) Overcomes Paclitaxel Resistance in ABCB1- and ABCC10-Overexpressing Cells and Tumors

Paclitaxel is one of the most widely used antineoplastic drugs in the clinic. Unfortunately, the occurrence of cellular resistance has limited its efficacy and application. The ATP-binding cassette subfamily B member 1 (ABCB1/P-glycoprotein) and subfamily C member 10 (ABCC10/MRP7) are the major membrane protein transporters responsible for the efflux of paclitaxel, constituting one of the most important mechanisms of paclitaxel resistance. Here, we demonstrated that the Bruton tyrosine kinase inhibitor, ibrutinib, significantly enhanced the antitumor activity of paclitaxel by antagonizing the efflux function of ABCB1 and ABCC10 in cells overexpressing these transporters. Furthermore, we demonstrated that the ABCB1 or ABCC10 protein expression was not altered after treatment with ibrutinib for up to 72 hours using Western blot analysis. However, the ATPase activity of ABCB1 was significantly stimulated by treatment with ibrutinib. Molecular docking analysis suggested the binding conformation of ibrutinib within the large cavity of the transmembrane region of ABCB1. Importantly, ibrutinib could effectively enhance paclitaxel-induced inhibition on the growth of ABCB1- and ABCC10-overexpressing tumors in nude athymic mice. These results demonstrate that the combination of ibrutinib and paclitaxel can effectively antagonize ABCB1- or ABCC10-mediated paclitaxel resistance that could be of great clinical interest. Mol Cancer Ther; 16(6); 1021–30. ©2017 AACR.

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Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor

Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases. JNJ-42756493 shows rapid uptake into the lysosomal compartment of cells in culture, which is associated with prolonged inhibition of FGFR signaling, possibly due to sustained release of the inhibitor. In xenografts from human tumor cell lines or patient-derived tumor tissue with activating FGFR alterations, JNJ-42756493 administration results in potent and dose-dependent antitumor activity accompanied by pharmacodynamic modulation of phospho-FGFR and phospho-ERK in tumors. The results of the current study provide a strong rationale for the clinical investigation of JNJ-42756493 in patients with tumors harboring FGFR pathway alterations. Mol Cancer Ther; 16(6); 1010–20. ©2017 AACR.

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Highlights of This Issue

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LACTB May Be a Tumor Suppressor Gene in Breast Cancer [Tumor Suppressors]

LACTB promotes breast cancer cell differentiation and suppresses breast tumorigenesis in vivo.

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LGR5+ Cancer Stem Cells Drive Primary and Metastatic Colorectal Cancer [Stem Cells]

LGR5⁺ colorectal cancer CSCs are dispensable for primary tumor growth due to plasticity.

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A FOXO4 Inhibitory Peptide Limits Chemotoxicity in Mice [Senescence]

The FOXO4 inhibitory peptide FOXO4-DRI promotes targeted apoptosis of senescent cells.

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ROCK Inhibition Primes Tumor Tissue to Sensitize Cells to Chemotherapy [Pancreatic Cancer]

Short-term ROCK targeting improves cytotoxic drug efficacy in primary and metastatic pancreatic cancers.

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Adoptive T-cell Transfer Targets Viral and Nonviral Tumor Antigens [Immunotherapy]

Successful T-cell therapy targets nonviral tumor antigens in patients with HPV⁺ cervical cancer.

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Indoximod Combo Triggers Responses in Melanoma [News in Brief]

Adding the investigational IDO-pathway inhibitor indoximod to checkpoint inhibitor therapy resulted in a 52% overall response rate in patients with advanced melanoma enrolled in a phase II trial. The combination strategy has potential as an alternative for patients whose tumors do not respond to standard therapy.

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Study Suggests Treatment Approaches for Cholangiocarcinomas [News in Brief]

A comprehensive genome profile of cholangiocarcinoma reveals that the tumors fall into four molecular classes. The study suggests that patients with IDH1/2 mutations could benefit from drugs that inhibit oxidative phosphorylation or that target mutations in chromatin remodeling genes. The work also shows that some liver cancers are closely related to cholangiocarcinomas.

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Targeting BRAF-Mutant Colorectal Cancer: Progress in Combination Strategies [In the Spotlight]

Summary: BRAF mutations in colorectal cancer portend a poor prognosis, with first-line treatment often involving triplet or quadruplet chemotherapy, and single-agent targeted therapy with BRAF inhibitors failing to demonstrate clinical activity. Blockade of multiple critical nodes along the MAPK and other pathways may be necessary to improve response rates and survival. Cancer Discov; 7(6); 558–60. ©2017 AACR.

See related article by van Geel et al., p. 610.

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Analysis Suggests Wider Use for PARP Inhibitors [News in Brief]

Researchers have developed a new tool, HRDetect, to pinpoint tumors that display BRCA deficiency but don't harbor BRCA1/2 mutations. Evaluating their method in breast, ovarian, and pancreatic cancers, they identified patients whose tumors were potentially vulnerable to PARP inhibition but who didn't carry these mutations.

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Noted [News in Brief]

A collection of recently published news items.

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CAR T-cell Therapy: Defining Response Characteristics [News in Brief]

Findings from a phase I study suggest that the durability of patients' response to CAR T-cell therapy, and their long-term survival, are influenced by whether they have minimal residual or morphologic disease prior to treatment. The former fared better overall, and also experienced less-severe side effects from this form of immunotherapy.

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An Anti-CD276 Antibody-Drug Conjugate Kills Tumor Cells and Vasculature [Drug Design]

An antibody–drug conjugate linking anti-CD276 to PBD dimers has antitumor and antimetastatic activity.

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Coxsackievirus A21 Synergizes with Checkpoint Inhibitors [News in Brief]

Treatment with a combination of a proprietary formulation of coxsackievirus and either an anti–CTLA-4 or anti–PD-1 checkpoint inhibitor yielded a higher response rate in phase I testing for melanoma than any of these drugs given on their own. Because the viral therapy adds little toxicity, it might prove an effective part of a dual regimen, according to interim trial data presented at the American Association for Cancer Research Annual Meeting 2017.

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Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers [Research Articles]

Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation–associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day.

Significance: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation–associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer. Cancer Discov; 7(6); 620–9. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 539

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Atezolizumab Extends Survival for Breast Cancer [News in Brief]

The anti–PD-L1 drug atezolizumab produced durable responses among 10% of patients with triple-negative breast cancer in a large phase I trial presented at the American Association for Cancer Research Annual Meeting 2017. The therapy proved safe, with the highest response rates seen in women who received the drug as a first-line therapy and in those with elevated PD-L1 levels and other tumor biomarkers.

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Exploiting Defective DNA Repair in IDH-Mutant Cancers [News in Brief]

Data from a preclinical study suggest rethinking the "oncometabolite hypothesis," which calls for blocking the product of neomorphic IDH1/2 mutations to halt tumor progression. Instead, exploiting the vulnerability of IDH1/2-mutant tumor cells to PARP inhibition, as a result of defective DNA repair, appears to be a more effective strategy that will soon be tested in the clinic.

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Immunotherapy Combo Offers Slight Survival Benefit in Melanoma [News in Brief]

Data on 2-year survival in the phase III CheckMate 067 trial testing nivolumab plus ipilimumab showed a slight survival benefit for the combination over nivolumab monotherapy—but the difference may not be dramatic enough to justify using the combination given the added side effects.

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SIRP{alpha}-CD47 Blockade-Mediated Tumor Cell Phagocytosis Requires SLAMF7 [Immunotherapy]

SLAMF7 expression is required for macrophage-mediated phagocytosis of hematopoietic tumor cells.

http://ift.tt/2qMLNbh

Profiling Differential Responses to Pan-HER Inhibition [News in Brief]

Findings from the phase II SUMMIT basket trial indicate that among patients with solid cancers harboring HER2/3 mutations, responses to the investigational pan-HER inhibitor neratinib vary by specific alteration and tumor type. Neratinib showed promising single-agent activity in breast, biliary tract, and cervical cancers, but was ineffective against bladder and colorectal cancers; among a small subset of patients with HER3 mutations, no responses were seen.

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Avelumab Impresses in Merkel Cell Carcinoma [News in Brief]

The PD-L1 inhibitor avelumab—approved by the FDA in March for the treatment of Merkel cell carcinoma—demonstrated a high number of durable responses in an international, open-label, prospective phase II study. The results of the study, which supported the FDA's decision, were presented in April at the American Association for Cancer Research (AACR) Annual Meeting 2017.

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LACTB May Be a Tumor Suppressor Gene in Breast Cancer [Tumor Suppressors]

LACTB promotes breast cancer cell differentiation and suppresses breast tumorigenesis in vivo.

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LGR5+ Cancer Stem Cells Drive Primary and Metastatic Colorectal Cancer [Stem Cells]

LGR5⁺ colorectal cancer CSCs are dispensable for primary tumor growth due to plasticity.

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A FOXO4 Inhibitory Peptide Limits Chemotoxicity in Mice [Senescence]

The FOXO4 inhibitory peptide FOXO4-DRI promotes targeted apoptosis of senescent cells.

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ROCK Inhibition Primes Tumor Tissue to Sensitize Cells to Chemotherapy [Pancreatic Cancer]

Short-term ROCK targeting improves cytotoxic drug efficacy in primary and metastatic pancreatic cancers.

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Adoptive T-cell Transfer Targets Viral and Nonviral Tumor Antigens [Immunotherapy]

Successful T-cell therapy targets nonviral tumor antigens in patients with HPV⁺ cervical cancer.

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Indoximod Combo Triggers Responses in Melanoma [News in Brief]

Adding the investigational IDO-pathway inhibitor indoximod to checkpoint inhibitor therapy resulted in a 52% overall response rate in patients with advanced melanoma enrolled in a phase II trial. The combination strategy has potential as an alternative for patients whose tumors do not respond to standard therapy.

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Study Suggests Treatment Approaches for Cholangiocarcinomas [News in Brief]

A comprehensive genome profile of cholangiocarcinoma reveals that the tumors fall into four molecular classes. The study suggests that patients with IDH1/2 mutations could benefit from drugs that inhibit oxidative phosphorylation or that target mutations in chromatin remodeling genes. The work also shows that some liver cancers are closely related to cholangiocarcinomas.

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Targeting BRAF-Mutant Colorectal Cancer: Progress in Combination Strategies [In the Spotlight]

Summary: BRAF mutations in colorectal cancer portend a poor prognosis, with first-line treatment often involving triplet or quadruplet chemotherapy, and single-agent targeted therapy with BRAF inhibitors failing to demonstrate clinical activity. Blockade of multiple critical nodes along the MAPK and other pathways may be necessary to improve response rates and survival. Cancer Discov; 7(6); 558–60. ©2017 AACR.

See related article by van Geel et al., p. 610.

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Analysis Suggests Wider Use for PARP Inhibitors [News in Brief]

Researchers have developed a new tool, HRDetect, to pinpoint tumors that display BRCA deficiency but don't harbor BRCA1/2 mutations. Evaluating their method in breast, ovarian, and pancreatic cancers, they identified patients whose tumors were potentially vulnerable to PARP inhibition but who didn't carry these mutations.

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Noted [News in Brief]

A collection of recently published news items.

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CAR T-cell Therapy: Defining Response Characteristics [News in Brief]

Findings from a phase I study suggest that the durability of patients' response to CAR T-cell therapy, and their long-term survival, are influenced by whether they have minimal residual or morphologic disease prior to treatment. The former fared better overall, and also experienced less-severe side effects from this form of immunotherapy.

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An Anti-CD276 Antibody-Drug Conjugate Kills Tumor Cells and Vasculature [Drug Design]

An antibody–drug conjugate linking anti-CD276 to PBD dimers has antitumor and antimetastatic activity.

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Coxsackievirus A21 Synergizes with Checkpoint Inhibitors [News in Brief]

Treatment with a combination of a proprietary formulation of coxsackievirus and either an anti–CTLA-4 or anti–PD-1 checkpoint inhibitor yielded a higher response rate in phase I testing for melanoma than any of these drugs given on their own. Because the viral therapy adds little toxicity, it might prove an effective part of a dual regimen, according to interim trial data presented at the American Association for Cancer Research Annual Meeting 2017.

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Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers [Research Articles]

Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation–associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day.

Significance: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation–associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer. Cancer Discov; 7(6); 620–9. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 539

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Atezolizumab Extends Survival for Breast Cancer [News in Brief]

The anti–PD-L1 drug atezolizumab produced durable responses among 10% of patients with triple-negative breast cancer in a large phase I trial presented at the American Association for Cancer Research Annual Meeting 2017. The therapy proved safe, with the highest response rates seen in women who received the drug as a first-line therapy and in those with elevated PD-L1 levels and other tumor biomarkers.

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Exploiting Defective DNA Repair in IDH-Mutant Cancers [News in Brief]

Data from a preclinical study suggest rethinking the "oncometabolite hypothesis," which calls for blocking the product of neomorphic IDH1/2 mutations to halt tumor progression. Instead, exploiting the vulnerability of IDH1/2-mutant tumor cells to PARP inhibition, as a result of defective DNA repair, appears to be a more effective strategy that will soon be tested in the clinic.

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Immunotherapy Combo Offers Slight Survival Benefit in Melanoma [News in Brief]

Data on 2-year survival in the phase III CheckMate 067 trial testing nivolumab plus ipilimumab showed a slight survival benefit for the combination over nivolumab monotherapy—but the difference may not be dramatic enough to justify using the combination given the added side effects.

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SIRP{alpha}-CD47 Blockade-Mediated Tumor Cell Phagocytosis Requires SLAMF7 [Immunotherapy]

SLAMF7 expression is required for macrophage-mediated phagocytosis of hematopoietic tumor cells.

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Profiling Differential Responses to Pan-HER Inhibition [News in Brief]

Findings from the phase II SUMMIT basket trial indicate that among patients with solid cancers harboring HER2/3 mutations, responses to the investigational pan-HER inhibitor neratinib vary by specific alteration and tumor type. Neratinib showed promising single-agent activity in breast, biliary tract, and cervical cancers, but was ineffective against bladder and colorectal cancers; among a small subset of patients with HER3 mutations, no responses were seen.

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Avelumab Impresses in Merkel Cell Carcinoma [News in Brief]

The PD-L1 inhibitor avelumab—approved by the FDA in March for the treatment of Merkel cell carcinoma—demonstrated a high number of durable responses in an international, open-label, prospective phase II study. The results of the study, which supported the FDA's decision, were presented in April at the American Association for Cancer Research (AACR) Annual Meeting 2017.

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INPP4B and PTEN Loss Leads to PI-3,4-P2 Accumulation and Inhibition of PI3K in TNBC

Triple-negative breast cancer [TNBC, lacks expression of estrogen receptor (ER), progesterone receptor (PR), and amplification of HER2/Neu] remains one of the most aggressive subtypes, affects the youngest patients, and still lacks an effective targeted therapy. Both phosphatidylinositol-3-kinase (PI3K)-α and -β contribute to oncogenesis of solid tumors, including the development of breast cancer. Inositol polyphosphate-4-phosphatase type II (INPP4B) catalyzes the removal of the 4'-phosphate of phosphatidylinositol-(3, 4)-bisphosphate (PI-3,4-P2), creating phosphatidylinositol-3-phosphate. There is debate concerning whether PI-3,4-P2 contributes to Akt and downstream effector activation with the known canonical signaling second messenger, phosphatidylinositol-(3, 4, 5)-trisphosphate (PIP3). If PI-3,4-P2 is a positive effector, INPP4B would be a negative regulator of PI3K signaling, and there is some evidence to support this. Utilizing phosphatase and tensin homolog deleted on chromosome ten (PTEN)-null triple-negative breast tumor cell lines, it was unexpectedly found that silencing INPP4B decreased basal phospho-Akt (pAkt) and cellular proliferation, and in most cases sensitized cells to PI3K-α and PI3K-β isoform-specific inhibitors. Conversely, overexpression of INPP4B desensitized cells to PI3K inhibitors in a phosphatase activity-dependent manner. In summary, the current investigation of INPP4B in PTEN-null TNBC suggests new mechanistic insight and the potential for targeted therapy for this aggressive subset of breast cancer.

Implications: These data support a model where PI-3,4-P2 is inhibitory toward PI3K, revealing a novel feedback mechanism under conditions of excessive signaling, and potentially an indication for PI3K-β isoform-specific inhibitors in PTEN-null TNBC that have lost INPP4B expression. Mol Cancer Res; 15(6); 765–75. ©2017 AACR.

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Highlights of This Issue

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Cancer Immunotherapy: Whence and Whither

The current concepts and practice of cancer immunotherapy evolved from classical experiments that distinguished "self" from "non-self" and the finding that humoral immunity is complemented by cellular immunity. Elucidation of the biology underlying immune checkpoints and interactions between ligands and ligand receptors that govern the immune system's ability to recognize tumor cells as foreign has led to the emergence of new strategies that mobilize the immune system to reverse this apparent tolerance. Some of these approaches have led to new therapies such as the use of mAbs to interfere with the immune checkpoint. Others have exploited molecular technologies to reengineer a subset of T cells to directly engage and kill tumor cells, particularly those of B-cell malignancies. However, before immunotherapy can become a more effective method of cancer care, there are many challenges that remain to be addressed and hurdles to overcome. Included are manipulation of tumor microenvironment (TME) to enhance T effector cell infiltration and access to the tumor, augmentation of tumor MHC expression for adequate presentation of tumor associated antigens, regulation of cytokines and their potential adverse effects, and reduced risk of secondary malignancies as a consequence of mutations generated by the various forms of genetic engineering of immune cells. Despite these challenges, the future of immunotherapy as a standard anticancer therapy is encouraging. Mol Cancer Res; 15(6); 635–50. ©2017 AACR.

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Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1

Doublecortin-like kinase 1 (DCLK1), a marker for intestinal and pancreatic cancer stem cells, is highly expressed in neuroblastomas. This study was conducted to assess DCLK1 expression levels in pancreatic neuroendocrine tumor (PNET) tissues and to explore the roles of this molecule in clinical tissue from multiple PNET patients, cells (BON1, QGP1, and CM) and tumor xenografts. Immunohistochemically, all PNET tissues highly and diffusely expressed DCLK1 as a full-length isoform, identical to that detected in primary liver NETs. A DCLK1-overexpressing PNET cell line (QGP1-DCLK1) exhibited epithelial–mesenchymal transition (EMT)-related gene signatures, and robust upregulation of Slug (SNAI2), N-Cadherin (CDH2), and Vimentin (VIM) was validated by real-time PCR and immunoblotting. QGP1-DCLK1 cells had increased cell migration in a wound-healing assay and formed significantly larger xenograft tumors in nude mice. The factors involved in the formation of the fast-growing tumors included p-FAK (on Tyr925), p-ERK1/2, p-AKT, Paxillin, and Cyclin D1, which upon knockdown or pharmacologic inhibition of DCLK1 abolished the expression of these molecules. In conclusion, robust and ubiquitous expression of DCLK1 was first demonstrated here in human PNET tissue specimens and cells. DCLK1 characterized the PNET cell behavior, inducing p-FAK/SLUG-mediated EMT. These findings suggest the possibility of developing novel therapeutic strategies against PNETs by targeting DCLK1.

Implications: Evidence here reveals that human PNETs diffusely and robustly express the cancer stem cell marker DCLK1, which drives SLUG-mediated EMT, and suggests that NETs share biological features for druggable targets with other tumors, including neuroblastoma that also highly expresses DCLK1. Mol Cancer Res; 15(6); 744–52. ©2017 AACR.

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The E3 Ligase CHIP Mediates p21 Degradation to Maintain Radioresistance

Lung cancer resists radiotherapy, making it one of the deadliest forms of cancer. Here, we show that human lung cancer cell lines can be rendered sensitive to ionizing radiation (IR) by RNAi knockdown of C-terminus of Hsc70-interacting protein (CHIP/STUB1), a U-box-type E3 ubiquitin ligase that targets a number of stress-induced proteins. Mechanistically, ubiquitin-dependent degradation of the cyclin-dependent kinase (CDK) inhibitor, p21 protein, is reduced by CHIP knockdown, leading to enhanced senescence of cells in response to exposure to IR. Cellular senescence and sensitivity to IR is prevented by CRISPR/Cas9-mediated deletion of the p21 gene (CDKN1A) in CHIP knockdown cells. Conversely, overexpression of CHIP potentiates p21 degradation and promotes greater radioresistance of lung cancer cells. In vitro and cell-based assays demonstrate that p21 is a novel and direct ubiquitylation substrate of CHIP that also requires the CHIP-associated chaperone HSP70. These data reveal that the inhibition of the E3 ubiquitin ligase CHIP promotes radiosensitivity, thus suggesting a novel strategy for the treatment of lung cancer.

Implications: The CHIP-HSP70-p21 ubiquitylation/degradation axis identified here could be exploited to enhance the efficacy of radiotherapy in patients with non–small cell lung cancer. Mol Cancer Res; 15(6); 651–9. ©2017 AACR.

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Hypoxia Selectively Enhances Integrin {alpha}5{beta}1 Receptor Expression in Breast Cancer to Promote Metastasis

Metastasis is the leading cause of breast cancer mortality. Previous studies have implicated hypoxia-induced changes in the composition and stiffness of the extracellular matrix (ECM) in the metastatic process. Therefore, the contribution of potential ECM-binding receptors in this process was explored. Using a bioinformatics approach, the expression of all integrin receptor subunits, in two independent breast cancer patient datasets, were analyzed to determine whether integrin status correlates with a validated hypoxia-inducible gene signature. Subsequently, a large panel of breast cancer cell lines was used to validate that hypoxia induces the expression of integrins that bind to collagen (ITGA1, ITGA11, ITGB1) and fibronectin (ITGA5, ITGB1). Hypoxia-inducible factors (HIF-1 and HIF-2) are directly required for ITGA5 induction under hypoxic conditions, which leads to enhanced migration and invasion of single cells within a multicellular 3D tumor spheroid but did not affect migration in a 2D microenvironment. ITGB1 expression requires HIF-1α, but not HIF-2α, for hypoxic induction in breast cancer cells. ITGA5 (α₅ subunit) is required for metastasis to lymph nodes and lungs in breast cancer models, and high ITGA5 expression in clinical biopsies is associated with an increased risk of mortality.

Implications: These results reveal that targeting ITGA5 using inhibitors that are currently under consideration in clinical trials may be beneficial for patients with hypoxic tumors. Mol Cancer Res; 15(6); 723–34. ©2017 AACR.

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CDK4/6 Therapeutic Intervention and Viable Alternative to Taxanes in CRPC

Resistance to second-generation androgen receptor (AR) antagonists and CYP17 inhibitors in patients with castration-resistant prostate cancer (CRPC) develops rapidly through reactivation of the androgen signaling axis and has been attributed to AR overexpression, production of constitutively active AR splice variants, or the selection for AR mutants with altered ligand-binding specificity. It has been established that androgens induce cell-cycle progression, in part, through upregulation of cyclin D1 (CCND1) expression and subsequent activation of cyclin-dependent kinases 4 and 6 (CDK4/6). Thus, the efficacy of the newly described CDK4/6 inhibitors (G1T28 and G1T38), docetaxel and enzalutamide, was evaluated as single agents in clinically relevant in vitro and in vivo models of hormone-sensitive and treatment-resistant prostate cancer. CDK4/6 inhibition (CDK4/6i) was as effective as docetaxel in animal models of treatment-resistant CRPC but exhibited significantly less toxicity. The in vivo effects were durable and importantly were observed in prostate cancer cells expressing wild-type AR, AR mutants, and those that have lost AR expression. CDK4/6i was also effective in prostate tumor models expressing the AR-V7 variant or the AR F876L mutation, both of which are associated with treatment resistance. Furthermore, CDK4/6i was effective in prostate cancer models where AR expression was lost. It is concluded that CDK4/6 inhibitors are a viable alternative to taxanes as therapeutic interventions in endocrine therapy–refractory CRPC.

Implications: The preclinical efficacy of CDK4/6 monotherapy observed here suggests the need for near-term clinical studies of these agents in advanced prostate cancer. Mol Cancer Res; 15(6); 660–9. ©2017 AACR.

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Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior

Commonly upregulated in human cancers, the scaffolding protein NEDD9/HEF1 is a known regulator of mesenchymal migration and cancer cell plasticity. However, the functional role of NEDD9 as a regulator of different migration/invasion modes in the context of breast cancer metastasis is currently unknown. Here, it is reported that NEDD9 is necessary for both mesenchymal and amoeboid individual cell migration/invasion in triple-negative breast cancer (TNBC). NEDD9 deficiency results in acquisition of the amoeboid morphology, but severely limits all types of cell motility. Mechanistically, NEDD9 promotes mesenchymal migration via VAV2-dependent Rac1 activation, and depletion of VAV2 impairs the ability of NEDD9 to activate Rac1. In addition, NEDD9 supports a mesenchymal phenotype through stimulating polymerization of actin via promoting CTTN phosphorylation in an AURKA-dependent manner. Interestingly, an increase in RhoA activity in NEDD9-depleted cells does not facilitate a switch to functional amoeboid motility, indicating a role of NEDD9 in the regulation of downstream RhoA signaling effectors. Simultaneous depletion of NEDD9 or inhibition of AURKA in combination with inhibition of the amoeboid driver ROCK results in an additional decrease in cancer cell migration/invasion. Finally, we confirmed that a dual targeting strategy is a viable and efficient therapeutic approach to hinder the metastasis of breast cancer in xenograft models, showcasing the important need for further clinical evaluation of this regimen to impede the spread of disease and improve patient survival.

Implications: This study provides new insight into the therapeutic benefit of combining NEDD9 depletion with ROCK inhibition to reduce tumor cell dissemination and discovers a new regulatory role of NEDD9 in the modulation of VAV2-dependent activation of Rac1 and actin polymerization. Mol Cancer Res; 15(6); 670–82. ©2017 AACR.

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Atorvastatin Decreases HBx-Induced Phospho-Akt in Hepatocytes via P2X Receptors

Hepatocellular carcinoma (HCC) is rated as the fifth most common malignancy and third in cancer-related deaths worldwide. Statins, HMG-CoA reductase inhibitors, are potent cholesterol-lowering drugs, and recent epidemiologic evidence suggests that statins prevent aggressive HCC development. Previous experiments revealed that statins downregulate phosphorylated Akt (pAkt). Here, it is demonstrated that atorvastatin decreases nuclear pAkt levels in pancreatic and lung cancer cell lines within minutes, and this rapid effect is mediated by the purinergic P2X receptors. Akt is upregulated by hepatitis viruses and has oncogenic activity in HCC; therefore, we tested the possibility that the P2X–Akt pathway is important for the anticipated anticancer effects of statins in hepatocytes. Atorvastatin decreased hepatitis B virus X protein- and insulin-induced pAkt and pGsk3β (Ser9) levels. Furthermore, Akt-induced lipogenesis was counteracted by atorvastatin, and these statin-induced effects were dependent on P2X receptors. Statin also decreased proliferation and invasiveness of hepatocytes. These data provide mechanistic evidence for a P2X receptor–dependent signaling pathway by which statins decrease pAkt, its downstream phosphorylation target pGsk3β, and lipogenesis in hepatocytes.

Implications: The Akt pathway is deregulated and may act as a driver in HCC development; the P2X–Akt signaling pathway may have a role in anticancer effects of statins. Mol Cancer Res; 15(6); 714–22. ©2017 AACR.

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Expression Profiling of Circulating Microvesicles Reveals Intercellular Transmission of Oncogenic Pathways

Circulating microvesicles have been described as important players in cell-to-cell communication carrying biological information under normal or pathologic condition. Microvesicles released by cancer cells may incorporate diverse biomolecules (e.g., active lipids, proteins, and RNA), which can be delivered and internalized by recipient cells, potentially altering the gene expression of recipient cells and eventually impacting disease progression. Leukemia in vitro model systems were used to investigate microvesicles as vehicles of protein-coding messages. Several leukemic cells (K562, LAMA-87, TOM-1, REH, and SHI-1), each carrying a specific chromosomal translocation, were analyzed. In the leukemic cells, these chromosomal translocations are transcribed into oncogenic fusion transcripts and the transfer of these transcripts was monitored from leukemic cells to microvesicles for each of the cell lines. Microarray gene expression profiling was performed to compare transcriptomes of K562-derived microvesicles and parental K562 cells. The data show that oncogenic BCR-ABL1 transcripts and mRNAs related to basic functions of leukemic cells were included in microvesicles. Further analysis of microvesicles cargo revealed a remarkable enrichment of transcripts related to cell membrane activity, cell surface receptors, and extracellular communication when compared with parental K562 cells. Finally, coculturing of healthy mesenchymal stem cells (MSC) with K562-derived microvesicles displayed the transfer of the oncogenic message, and confirmed the increase of target cell proliferation as a function of microvesicle dosage.

Implications: This study provides novel insight into tumor-derived microvesicles as carriers of oncogenic protein–coding messages that can potentially jeopardize cell-directed therapy, and spread to other compartments of the body. Mol Cancer Res; 15(6); 683–95. ©2017 AACR.

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The Cytidine Deaminase APOBEC3 Family Is Subject to Transcriptional Regulation by p53

The APOBEC3 (A3) family of proteins are DNA cytidine deaminases that act as sentinels in the innate immune response against retroviral infections and are responsive to IFN. Recently, a few A3 genes were identified as potent enzymatic sources of mutations in several human cancers. Using human cancer cells and lymphocytes, we show that under stress conditions and immune challenges, all A3 genes are direct transcriptional targets of the tumor suppressor p53. Although the expression of most A3 genes (including A3C and A3H) was stimulated by the activation of p53, treatment with the DNA-damaging agent doxorubicin or the p53 stabilizer Nutlin led to repression of the A3B gene. Furthermore, p53 could enhance IFN type-I induction of A3 genes. Interestingly, overexpression of a group of tumor-associated p53 mutants in TP53-null cancer cells promoted A3B expression. These findings establish that the "guardian of the genome" role ascribed to p53 also extends to a unique component of the immune system, the A3 genes, thereby integrating human immune and chromosomal stress responses into an A3/p53 immune axis.

Implications: Activated p53 can integrate chromosomal stresses and immune responses through its influence on expression of APOBEC3 genes, which are key components of the innate immune system that also influence genomic stability. Mol Cancer Res; 15(6); 735–44. ©2017 AACR.

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CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States, whereas colorectal cancer is the third most common cancer. The RNA-binding protein HuR (ELAVL1) supports a pro-oncogenic network in gastrointestinal (GI) cancer cells through enhanced HuR expression. Using a publically available database, HuR expression levels were determined to be increased in primary PDA and colorectal cancer tumor cohorts as compared with normal pancreas and colon tissues, respectively. CRISPR/Cas9 technology was successfully used to delete the HuR gene in both PDA (MIA PaCa-2 and Hs 766T) and colorectal cancer (HCT116) cell lines. HuR deficiency has a mild phenotype, in vitro, as HuR-deficient MIA PaCa-2 (MIA.HuR-KO^(–/–)) cells had increased apoptosis when compared with isogenic wild-type (MIA.HuR-WT^(+/+)) cells. Using this isogenic system, mRNAs were identified that specifically bound to HuR and were required for transforming a two-dimensional culture into three dimensional (i.e., organoids). Importantly, HuR-deficient MIA PaCa-2 and Hs 766T cells were unable to engraft tumors in vivo compared with control HuR-proficient cells, demonstrating a unique xenograft lethal phenotype. Although not as a dramatic phenotype, CRISPR knockout HuR HCT116 colon cancer cells (HCT.HuR-KO^(–/–)) showed significantly reduced in vivo tumor growth compared with controls (HCT.HuR-WT^(+/+)). Finally, HuR deletion affects KRAS activity and controls a subset of pro-oncogenic genes.

Implications: The work reported here supports the notion that targeting HuR is a promising therapeutic strategy to treat GI malignancies. Mol Cancer Res; 15(6); 696–707. ©2017 AACR.

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Phosphatidylserine Sensing by TAM Receptors Regulates AKT-Dependent Chemoresistance and PD-L1 Expression

Tyro3, Axl, and Mertk (collectively TAM receptors) are three homologous receptor tyrosine kinases that bind vitamin K–dependent endogenous ligands, Protein S (ProS), and growth arrest–specific factor 6 (Gas6), and act as bridging molecules to promote phosphatidylserine (PS)-mediated clearance of apoptotic cells (efferocytosis). TAM receptors are overexpressed in a vast array of tumor types, whereby the level of expression correlates with the tumor grade and the emergence of chemo- and radioresistance to targeted therapeutics, but also have been implicated as inhibitory receptors on infiltrating myeloid-derived cells in the tumor microenvironment that can suppress host antitumor immunity. In the present study, we utilized TAM-IFNR1 reporter lines and expressed TAM receptors in a variety of epithelial cell model systems to show that each TAM receptor has a unique pattern of activation by Gas6 or ProS, as well as unique dependency for PS on apoptotic cells and PS liposomes for activity. In addition, we leveraged this system to engineer epithelial cells that express wild-type TAM receptors and show that although each receptor can promote PS-mediated efferocytosis, AKT-mediated chemoresistance, as well as upregulate the immune checkpoint molecule PD-L1 on tumor cells, Mertk is most dominant in the aforementioned pathways. Functionally, TAM receptor–mediated efferocytosis could be partially blocked by PS-targeting antibody 11.31 and Annexin V, demonstrating the existence of a PS/PS receptor (i.e., TAM receptor)/PD-L1 axis that operates in epithelial cells to foster immune escape. These data provide a rationale that PS-targeting, anti–TAM receptor, and anti–PD-L1-based therapeutics will have merit as combinatorial checkpoint inhibitors.

Implications: Many tumor cells are known to upregulate the immune checkpoint inhibitor PD-L1. This study demonstrates a role for PS and TAM receptors in the regulation of PD-L1 on cancer cells. Mol Cancer Res; 15(6); 753–64. ©2017 AACR.

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