Cancers Evade Immunotherapy by ‘Discarding the Evidence’ of Tumor-Specific Mutations

Excerpt:

“Results of an initial study of tumors from patients with lung cancer or head and neck cancer suggest that the widespread acquired resistance to immunotherapy drugs known as checkpoint inhibitors may be due to the elimination of certain genetic mutations needed to enable the immune system to recognize and attack malignant cells. The study, conducted by researchers on the cells of five of their patients treated at the Johns Hopkins Kimmel Cancer Center, is described online Dec. 28 in Cancer Discovery.”

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Moffitt Researchers Develop a Novel Cancer Treatment Approach Based on Evolutionary Principals to Inhibit Chemo-Resistance, Prolong Progression-Free Survival

“Despite numerous advances in oncology since the War on Cancer began, many patients develop resistance to standard therapies and eventually relapse. Moffitt Cancer Center researchers hope to improve treatment outcomes with development of a novel therapeutic strategy, called adaptive therapy, which is based on evolutionary principals and aims to keep resistant cells in check by maintaining a population of chemo-sensitive cells.

“The standard strategy for administering cancer chemotherapy has changed very little over the past five decades.  Cancer drug are typically given at the maximum tolerated dose that a patient can tolerate without any life-threatening toxicity.  While this strategy works very effectively at killing cancer cells in the short-term, once the chemo-sensitive cells are removed, existing chemo-resistant cells survive and then continue to grow and divide despite the ongoing therapy.”


No Benefit of Adding Gefitinib to Platinum-Based Doublet in EGFR-Mutant NSCLC After Progression on First-Line Gefitinib

“In a phase III IMPRESS trial reported in The Lancet Oncology, Soria et al found no progression-free survival benefit of adding gefitinib (Iressa) to platinum-based doublet chemotherapy in patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC) who had acquired resistance to first-line gefitinib.

“In the double-blind trial, 265 chemotherapy-naive patients from 11 countries who had stage IIIB to IV EGFR-mutant disease and disease control with first-line gefitinib and recent disease progression took part. They were randomly assigned between March 2012 and December 2013 to receive cisplatin 75 mg/m2 plus pemetrexed (Alimta) 500 mg/m2 on the first day of a maximum of six chemotherapy cycles plus either daily gefitinib 250 mg (n = 133) or placebo (n = 132) continued until disease progression or discontinuation for other reasons…

“The investigators concluded: ‘Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting.’ ”


On the Failure of Lung Cancer Drug Onartuzumab in a Phase III Clinical Trial


Most new cancer drugs fail clinical testing. Because they don’t make it to the pharmacy, we usually hear very little about them. But widespread media coverage made it hard to ignore the recent termination of a trial testing the drug onartuzumab. Details of the story raise concerns about the patient enrollment processes of some clinical trials. Continue reading…


Melanoma: A 2013 ‘Progress Report’


The past year saw some remarkable advances in melanoma clinical research and treatment. This feature explores the most notable melanoma news of 2013: Continue reading…


Cotargeting Androgen Receptor and Clusterin Delays Castrate-Resistant Prostate Cancer Progression by Inhibiting Adaptive Stress Response and AR Stability

“Although androgen receptor (AR) pathway inhibitors prolong survival in castrate-resistant prostate cancer (CRPC), resistance rapidly develops and is often associated with increased stress-activated molecular chaperones like clusterin (CLU) and continued AR signaling. Because adaptive pathways activated by treatment facilitate development of acquired resistance, cotargeting the stress response, activated by AR inhibition and mediated through CLU, may create conditional lethality and improve outcomes. Here, we report that CLU is induced by AR antagonism and silencing using MDV3100 and antisense, respectively, to become highly expressed in castrate- and MDV3100-resistant tumors and cell lines. CLU, as well as AKT and mitogen-activated protein kinase (MAPK) signalosomes, increase in response to MDV3100-induced stress. Mechanistically, this stress response is coordinated by a feed-forward loop involving p90rsk (RPS6KA)-mediated phosphoactivation of YB-1 with subsequent induction of CLU. CLU inhibition repressed MDV3100-induced activation of AKT and MAPK pathways. In addition, when combined with MDV3100, CLU knockdown accelerated AR degradation and repressed AR transcriptional activity through mechanisms involving decreased YB-1–regulated expression of the AR cochaperone, FKBP52. Cotargeting the AR (with MDV3100) and CLU (with OGX-011) synergistically enhanced apoptotic rates over that seen with MDV3100 or OGX-011 monotherapy and delayed CRPC LNCaP tumor and prostate-specific antigen (PSA) progression in vivo. These data indicate that cotargeting adaptive stress pathways activated by AR pathway inhibitors, and mediated through CLU, creates conditional lethality and provides mechanistic and preclinical proof-of-principle to guide biologically rational combinatorial clinical trial design.”


Diabetes Plus Anticancer Drug Combination Targets Melanoma Cells Unresponsive to Standard Treatments


Researchers at the Wistar Institute in Philadelphia, Pennsylvania, recently developed a combination approach to target melanoma tumor cells that are particularly resistant to both chemotherapy and targeted therapies, such as vemurafenib. A combination of anti-melanoma drugs with an anti-diabetes drug was better able to target all of the cells in a tumor than the anti-melanoma drugs alone. The combination therapy even proved effective against cells that are usually resistant to therapy and are thought to be responsible for at least some of the resistance patients develop to melanoma treatment. Continue reading…


Collaborative Effort Aims to Find Strategies to Preempt Resistance to Prostate Cancer Therapies


The ‘Targeting Adaptive Pathways in Metastatic Treatment-Resistant Prostate Cancer’ 3-year project aims to understand how prostate tumors become resistant to two newer drugs for prostate cancer that target the androgen receptor pathway—enzalutamide and abiraterone acetate. Continue reading…


Simultaneous Spurts of Mutations Drive Prostate Cancer, Whole-Genome Sequencing Study Finds


A large collaborative research effort shows that prostate cancers may evolve in sudden, brief spurts of many simultaneous genetic mutations that disrupt important prostate cancer genes. Using deep-sequencing techniques and computer modeling, scientists have created a detailed temporal map of how genetic aberrations evolve within prostate tumors. This result differs from the traditional model of cancer resulting from the step-by-step accumulation of individual mutations. The study is published in the journal Cell. Continue reading…