Therapeutic RANKL inhibition reduces cancer stem cells

RANK expression is associated with poor prognosis in breast cancer even though its therapeutic potential remains unknown. RANKL and its receptor RANK are downstream effectors of the progesterone signaling pathway. However, RANK expression is enriched in hormone receptor negative adenocarcinomas suggesting additional roles for RANK signaling beyond its hormone-dependent function. Here, to explore the role of RANK signaling once tumors have developed we use the mouse mammary tumor virus- Polyoma Middle T (MMTV-PyMT) which mimics RANK and RANKL expression patterns seen in human breast adenocarcinomas. Complementary genetic and pharmacological approaches demonstrate that therapeutic inhibition of RANK signaling drastically reduces the cancer stem cell pool, decreases tumor and metastasis initiation and enhances sensitivity to chemotherapy. Mechanistically, genome wide expression analyses showed that anti-RANKL therapy promotes lactogenic differentiation of tumor cells. Moreover, RANK signaling in tumor cells negatively regulates the Ap2 transcription factors, and enhances the Wnt agonist Rspo1 and the Sca1- population, enriched in tumor initiating cells. Additionally, we found that expression of TFAP2B and the RANK inhibitor, OPG, in human breast cancer correlate and are associated with relapse free tumors. These results support the use of RANKL inhibitors to reduce recurrence and metastasis in breast cancer patients based on its ability to induce tumor cell differentiation.

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ctDNA dynamic patterns and response to TIL immunotherapy

Purpose:Adoptive transfer of activated autologous tumor-infiltrating lymphocytes (TIL) can mediate complete, durable regressions in patients with metastatic melanoma (MM). Responding patients generally do not have significant changes in non-cutaneous RECIST targets before 30-60 days following TIL infusion, and complete responses are often not confirmed for 1-2 years. There is a critical need for a biomarker that can provide early information regarding the likelihood and duration of a response to enable rational decisions about altering therapy. We wished to evaluate the role of ctDNA in separating responding from non-responding patients. Experimental Design:We studied BRAF V600E ctDNA levels by a sensitive allele specific PCR assay in 388 serum samples from 48 patients who received TIL immunotherapy at the National Cancer Institute, and correlated differences in the dynamic patterns of their ctDNA measurements with response outcomes. Results:A strong correlation was found between the presence or absence of an early serum peak of V600E ctDNA, and the likelihood of an objective response. Furthermore, patients that developed an early ctDNA peak and cleared their serum of V600E ctDNA were highly likely to achieve a complete response over the next 1-2 years. Patients that showed no peak of V600E ctDNA failed to achieve an objective response, with one exception. Conclusions:We show that the dynamic changes occurring in BRAF V600E ctDNA levels within the first month following T-cell transfer immunotherapy in MM can be used to rapidly identify responding from non-responding patients, potentially allowing clinicians to make critical treatment-related decisions in a more timely manner. These data also suggest that the majority of tumor killing by TIL occurs very early after the initiation of therapy.

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UPF1 Mutations Suppress Nonsense-Mediated RNA Decay in IMT [Tumorigenesis]

Inflammatory myofibroblastic tumors (IMT) harbor mutations in nonsense-mediated RNA decay gene UPF1.

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Enhancing PD-1 Blockade in Solid Tumors [News in Brief]

A phase I study indicates that the combination of utomilumab, an investigational antibody that binds CD137, plus pembrolizumab is safe and well tolerated, yielding sustained responses in patients with various solid cancers.

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A Ubiquitin-Independent Function of CRBN Mediates the Response to IMiDs [Myelodysplastic Syndrome]

CRBN promotes CD147–MCT1-mediated antitumor activity in response to IMiDs.

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Pancreatic Cancer Survival Increases with Chemo Combo [News in Brief]

For patients able to have surgery for pancreatic cancer, the adjuvant use of gemcitabine plus capecitabine, instead of gemcitabine alone, leads to a significant improvement in 5-year survival, according to results of the ESPAC-4 trial. The finding will likely change the standard of care for these patients.

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DRD4 Selectively Promotes Glioblastoma Stem Cell Growth [Glioblastoma]

Dopamine receptor D4 (DRD4) is a potential therapeutic target in glioblastoma stem cells.

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Biomarker-Driven Treatments Yield Better Results [News in Brief]

According to a meta-analysis of 351 phase I trials, choosing a therapy based on the abnormalities that drive a tumor yields higher response rates than therapeutic selections that aren't biomarker-driven.

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RASSF1A Represses TGF{beta} Oncogenic Signaling via YAP1/SMAD2 Translocation [Signaling]

TGFβ triggers RASSF1A ubiquitination to drive SMAD2-mediated transcription of TGFβ target genes.

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Tumor Profiling: Adding Proteomics to Genomics [News in Brief]

Researchers have used mass spectrometry to conduct proteomic analyses of 77 genomically characterized breast tumors. Through this approach, they've uncovered functional consequences of somatic mutations. For instance, EGFR overexpression in basal-like breast cancer is potentially driven by the loss of two genes, SKP1 and CETN3, from the chromosome 5q deletion characteristic of this disease subtype.

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Brain Tumors Under Therapy Undergo Highly Branched Clonal Evolution [Brain Tumors]

Glioblastomas exhibit highly branched, treatment-specific clonal evolution patterns.

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Blocking PD-1 in Tumors with Faulty DNA Repair [News in Brief]

A phase II study shows that DNA mismatch repair deficiency can render tumors highly sensitive to the PD-1 inhibitor pembrolizumab. Patients with a range of solid tumors, including colorectal and endometrial cancers, with the deficiency responded well and durably to immune checkpoint blockade, with minimal toxicity.

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Combining Antigen-Specific CTLs with Ipilimumab Is Effective in Melanoma [Immunotherapy]

MART1-specific CTLs followed by ipilimumab induce durable tumor regression in patients with melanoma.

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First-Line Atezolizumab Effective in Bladder Cancer [News in Brief]

Results from a phase II study indicate that the PD-L1 inhibitor atezolizumab, recently approved for advanced bladder cancer that's refractory to standard platinum chemotherapy, is effective as first-line therapy for this disease. Durable responses to atezolizumab were seen in nearly a quarter of the study patients, who were all ineligible to receive cisplatin.

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The Cytotoxic Effects of Lenalidomide Are Calcium- and Calpain-Dependent [Myelodysplastic Syndrome]

Calcium metabolism gene GPR68 mediates lenalidomide sensitivity in myelodysplastic syndrome (MDS).

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Antibody Improves Survival in Gastric Cancer [News in Brief]

Results from a randomized phase II study indicate that adding the experimental antibody IMAB362, which targets the tight junction protein claudin18.2, to standard chemotherapy is more effective than chemotherapy alone in previously untreated patients with advanced gastric cancer. IMAB362 extended progression-free and overall survival by 3.1 months and 4.8 months, respectively.

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The Cereblon Modulator CC-885 Exhibits Antitumor Activity [Structural Biology]

A common motif likely promotes binding of substrates, including GSPT1, to cereblon.

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Probing Biological Sex Differences in Cancer [News in Brief]

A comprehensive analysis of data from The Cancer Genome Atlas has shed light on molecular-level differences between men and women with cancer. The study researchers separated 13 cancers into "strong" and "weak" sex-effect groups; cancers in the former showed extensive sex-biased molecular signatures, including changes in a considerable number of clinically actionable genes.

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Nuclear p62 Inhibits the DNA Damage Response [DNA Repair]

Accumulation of nuclear p62, driven by loss of autophagy, decreases chromatin ubiquitination.

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Targeting DOT1L May Reverse Leukemogenic Effects of Mutant DNMT3A [Leukemia]

Mutant DNMT3A promotes leukemogenesis via aberrant epigenetic induction of stem-cell genes.

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CRISPR Screens for the Discovery of Cancer Vulnerabilities [Research Articles]

CRISPR/Cas9 has emerged as a powerful new tool to systematically probe gene function. We compared the performance of CRISPR to RNAi-based loss-of-function screens for the identification of cancer dependencies across multiple cancer cell lines. CRISPR dropout screens consistently identified more lethal genes than RNAi, implying that the identification of many cellular dependencies may require full gene inactivation. However, in two aneuploid cancer models, we found that all genes within highly amplified regions, including nonexpressed genes, scored as lethal by CRISPR, revealing an unanticipated class of false-positive hits. In addition, using a CRISPR tiling screen, we found that sgRNAs targeting essential domains generate the strongest lethality phenotypes and thus provide a strategy to rapidly define the protein domains required for cancer dependence. Collectively, these findings not only demonstrate the utility of CRISPR screens in the identification of cancer-essential genes, but also reveal the need to carefully control for false-positive results in chromosomally unstable cancer lines.

Significance: We show in this study that CRISPR-based screens have a significantly lower false-negative rate compared with RNAi-based screens, but have specific liabilities particularly in the interrogation of regions of genome amplification. Therefore, this study provides critical insights for applying CRISPR-based screens toward the systematic identification of new cancer targets. Cancer Discov; 6(8); 900–13. ©2016 AACR.

See related commentary by Sheel and Xue, p. 824.

See related article by Aguirre et al., p. 914.

This article is highlighted in the In This Issue feature, p. 803

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Reconstituting the Human Immune System [News in Depth]

Studying checkpoint blockers and other new immunotherapies is challenging in traditional mouse models because the animals lack B and T cells and have impaired innate immunity. To address these shortcomings, researchers are making progress in reconstituting the human immune system in immunodeficient mouse models.

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