Synergistic targeting of the regulatory and catalytic subunits of PI3K{delta} in mature B cell malignancies

Purpose: Aberrant activation of the B cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase delta). These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, towards identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies. Experimental Design: We used in vitro and in vivo diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) samples to pre-clinically evaluate the effects of the combination of the FDA-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast and idelalisib on cell survival and tumor growth. Genetic models of gain- and loss-of-function were employed to map multiple signaling intermediaries downstream of the BCR. Results: Roflumilast elevates the intracellular levels of cyclic-AMP and synergizes with idelalisib in suppressing tumor growth and PI3K activity. Mechanistically, we show that roflumilast suppresses PI3K by inhibiting BCR-mediated activation of the P85 regulatory subunit, distinguishing itself from idelalisib, an ATP-competitive inhibitor of the catalytic P110 subunit. Using genetic models, we linked the PDE4-regulated modulation of P85 activation to the oncogenic kinase SYK. Conclusions: These data demonstrate that roflumilast and idelalisib suppress PI3K by distinct mechanisms, explaining the basis for their synergism, and suggest that the repurposing of PDE4 inhibitors to treat BCR-dependent malignancies is warranted.

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Merkel cell carcinoma patients presenting without a primary lesion have elevated markers of immunity, higher tumor mutation burden and improved survival

Purpose: Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared to similarly staged patients with known primary lesions (MCC-KP). The basis of this previously reported finding is unclear. Experimental Design: Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole exome sequence data was analyzed from 16 tumors. Results: As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared to MCC-KP patients (HR 0.297, p < 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR 0.296, p = 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24%) patients with MCC-KP (p < 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; p < 0.001). Additionally, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, p = 0.016). Conclusions: This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC-UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. Additionally, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival.

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Ipilimumab plus Lenalidomide after Allogeneic and Autologous Stem Cell Transplantation for Patients with Lymphoid Malignancies

Purpose: Prevention or treatment of relapsed lymphoid malignancies after hematopoietic stem cell transplantation (HSCT) requires novel strategies. We hypothesized that anti-tumor-cell responses could be enhanced by the addition of lenalidomide to the cytotoxic T-lymphocyte-associated protein 4 inhibitor ipilimumab. Experimental Design: We conducted a phase 2 investigator-initiated trial to assess the safety and activity of ipilimumab and lenalidomide in patients with lymphoid malignancies that relapsed after allogeneic HSCT and in high-risk patients after autologous HSCT. Patients received 10 mg of oral lenalidomide daily for 21 days followed by intravenous ipilimumab at 3 mg/kg body weight. The regimen was repeated 4 weeks later for a total of 4 treatments. Results: We enrolled 17 patients (10 allogeneic and 7 autologous transplant recipients). Immune-mediated toxicity was limited to 1 patient with asymptomatic hypothyroidism and 1 with dermatitis in the allogeneic and autologous groups, respectively. One allogeneic transplant recipient had a flare of prior graft-versus-host disease (GVHD) while taking lenalidomide that precluded further treatment. All others finished treatment without GVHD. Four of 10 patients in the allogeneic group had complete responses (three of which were durable at 19+, 21+ and 32+ months), and 3 had partial responses. The disease in 6 of 7 patients in the autologous group remains in remission. The groups had similar immune responses; including a 2- to 3 -fold increases in inducible ICOS+CD4+FoxP3- T cells number. Conclusions:Our early-phase data suggested that ipilimumab plus lenalidomide is well tolerated after HSCT. Adverse events did not differ significantly between the allogeneic and autologous groups.

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Genome-wide association study identifies a new locus at 7q21.13 associated with hepatitis B virus-related hepatocellular carcinoma

Purpose: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In China, chronic hepatitis B virus (HBV) infection remains the major risk factor for HCC. In the present study, we performed a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci contributing to susceptibility to HBV-related HCC. Experimental Design: GWAS scan is performed in a collection of 205 HBV-related HCC trios (each trio includes an affected proband and his/her both parents), and 355 chronic HBV carriers with HCC (cases) and 360 chronic HBV carriers without HCC (controls), followed by two rounds of replication studies totally consisting of 3,796 cases and 2,544 controls. Results: We identified a novel association signal within the CDK14 gene at 7q21.13 (index rs10272859, odds ratio = 1.28, P = 9.46 x 10-10). Furthermore, we observed that the at-risk rs10272859[G] allele was significantly associated with higher mRNA expression levels of CDK14 in liver tissues. Chromosome conformation capture assays in liver cells confirmed that a physical interaction exists between the promoter region of CDK14 and the risk-associated SNPs in strong linkage disequilibrium with the index rs10273859 at 7q21.13. This index rs10272859 also showed significant association with the survival of HCC patients. Conclusions: Our findings highlight a novel locus at 7q21.13 conferring both susceptibility and prognosis to HBV-related HCC, and suggest the CDK14 gene to be the functional target of the 7q21.13 locus.

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Mitochondrial inhibition augments the efficacy of imatinib by resetting the metabolic phenotype of gastrointestinal stromal tumor

Purpose: Imatinib dramatically reduces GIST 18 F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown. Experimental Design: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered Kit V558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity. In vitro assays on human GIST cell lines were also performed. Results: Imatinib therapy decreased glucose uptake and downstream glycolytic activity in GIST-T1 and HG129 cells by approximately half and upregulated mitochondrial enzymes and improved mitochondrial respiratory capacity. Mitochondrial inhibition with VLX600 had a direct antitumor effect in vitro while appearing to promote glycolysis through increased AKT signaling and glucose transporter expression. When combined with imatinib, VLX600 prevented imatinib-induced cell cycle escape and reduced p27 expression, leading to increased apoptosis when compared to imatinib alone. In Kit V558del/+ mice, VLX600 alone did not induce tumor cell death, but had a profound antitumor effect when combined with imatinib. Conclusions: Our findings show that imatinib alters the metabolic phenotype of GIST and this may contribute to imatinib resistance. Our work offers preclinical proof of concept of metabolic targeting as an effective strategy for the treatment of GIST.

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Response to Immune Checkpoint Blockade is Influenced by HLA-I Genotype [Research Watch]

Maximal HLA-I loci heterozygosity is linked to improved survival after immune checkpoint blockade.

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YY1 Facilitates Enhancer-Promoter Contacts to Promote Gene Expression [Research Watch]

YY1 preferentially occupies active enhancers and promoters and forms dimers to promote DNA looping.

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