Drug Combination Targeting HSP90 and BRAF Is Safe and Effective in Advanced Melanoma


“Patients with advanced or metastatic melanoma have been able to live longer cancer-free lives because of several new therapies approved over the last decade, such as BRAF and MEK inhibitors. However, despite the success of these targeted agents, most patients eventually develop drug resistance and their cancer regrows. A team of researchers at Moffitt Cancer Center have been working to learn more about how melanoma becomes resistant to BRAF inhibitors in order to develop new treatment strategies. They tested whether a drug targeting heat shock protein 90 (HSP90) combined with the BRAF inhibitor vemurafenib could be a safe and potentially effective strategy to treat patients with melanoma. Their study was published online ahead of print in Clinical Cancer Research.”

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Combining Drugs May Help Fight Drug Resistance in Breast Cancer

Note: This article describes research that was done in a laboratory setting, and not in people. However, the drug combination (ganetespib plus hormone therapy) is being tested in patients in clinical trials.

“US researchers have found that combining conventional hormone therapy with an experimental cancer drug helped overcome drug resistance in breast cancer cells in the lab.

“The research focused on a molecular ‘Sherpa’ that helps cells adapt to stressful environments, known as heat-shock protein 90 (HSP90)…

“Trials of ganetespib in combination with hormone therapy are now underway in the US, and the researchers are hoping to see results within the next few years.”

Synta Announces Advancement of Ganetespib into Phase 3 Extension of AML LI-1 Study for Patients with AML and High-Risk MDS

The gist: Researchers are conducting a clinical trial with volunteer patients to test new treatments for newly diagnosed elderly patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) who, for whatever reason, cannot undergo intensive chemotherapy. One of the treatments being tested combines the drugs ganetespib and cytarabine. Based on promising results for patients from phase 2 of the trial, the combination treatment is advancing to phase 3, in which it will be tested in even more patients.

“Synta Pharmaceuticals Corp. SNTA +2.46% today announced the advancement of ganetespib into the Phase 3 extension of the AML LI-1 (less intensive) trial. AML LI-1 is a multicenter, randomized Phase 2/3 clinical study evaluating several novel treatment regimens, including the combination of ganetespib with low dose cytarabine (Ara-C), in newly diagnosed elderly patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) who are not eligible for intensive chemotherapy. Ganetespib is a next-generation inhibitor of the chaperone protein Hsp90, which is critical for the activation and stability of numerous proteins that drive cancer growth and proliferation. Ganetespib has been studied in over 1000 patients to date.

“Advancement into the Phase 3 extension follows an interim analysis of results from 50 patients who received the ganetespib-cytarabine combination in the Phase 2 portion of the trial. The primary efficacy outcome in Phase 2 was rate of complete response. Per protocol, the Phase 3 extension will include an interim futility analysis and enroll approximately 200 patients in the ganetespib-cytarabine and the cytarabine alone arms, for a total of approximately 400 patients. The primary efficacy endpoint for the Phase 3 extension will include overall survival. The Company is currently in discussion with study investigators, and anticipates providing additional details, including the timing of study milestones, as they become formalized.”

Synta Announces Results from Final Analysis of the GALAXY-1 Trial of Ganetespib in NSCLC

“Synta Pharmaceuticals Corp. (NASDAQ: SNTA) today announced final results from the GALAXY-1 trial, a global, randomized, multi-center study designed to identify the patients with advanced non-small cell lung cancer (NSCLC) with adenocarcinoma histology most likely to benefit from second-line treatment with the Company’s lead drug candidate, the Hsp90 inhibitor ganetespib, in combination with docetaxel versus docetaxel alone. Ganetespib is a next-generation inhibitor of the chaperone protein Hsp90, which is critical for the activation and stability of numerous proteins that drive cancer growth and proliferation. Ganetespib has been studied in over 1000 patients to date.”

Editor’s note: This story is about clinical trials designed to test the effectiveness of a drug called ganetespib in people with non-small cell lung cancer (NSCLC). The drug manufacturer (Synta) recently reported updated results for one of the trials, GALAXY-1. The results confirm that the researchers were able to identify patients who were most likely to benefit from a treatment that combines ganetespib with the chemotherapy drug docetaxel.

Trial Results for New Lung Cancer Drug Ganetespib Leave Some Skeptical

The GALAXY-1 clinical trial examines patients with advanced lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC), receiving either ganetespib (a new cancer drug) and docetaxel (Taxotere, a chemotherapy drug) or Taxotere alone as second-line treatment. Recent interim results show ganetespib-treated patients surviving 10.4 months on average (vs 8.4 months in the Taxotere-only group) and experiencing a 10% reduction in the risk of death. This is a smaller difference than was seen in preliminary results in September, 2012 and June, 2013 (31% and 18% reduction in risk of death, respectively). It is also unclear whether the effect is indeed caused by ganetespib or due to chance. However, the drug’s makers emphasize that ganetespib may be more effective in certain patient subgroups.

FDA Puts Lung Cancer Drug Ganetespib on Fast Track

Ganetespib, a potential new treatment for non-small cell lung cancer (NSCLC), has been granted Fast Track status by the U.S. Food and Drug Administration (FDA). Fast Track status, reserved for drugs aimed at serious conditions with unmet treatment needs, provides for closer FDA guidance during the drug development process and quicker review for approval. Two clinical trials, GALAXY-1 and GALAXY-2, are currently examining the use of ganetespib in combination with the chemotherapy agent Taxotere (docetaxel) for treating advanced lung adenocarcinoma, a type of NSCLC. Ganetespib acts by blocking Hsp90, a protein that facilitates several components of tumor development and spread.

Inhibition of HSP90 molecular chaperones: moving into the clinic

“Heat shock protein 90 (HSP90) is a molecular chaperone that is crucial for the stability and function of many proteins essential for cell survival. Many oncogenes are client proteins of HSP90. Inhibition of HSP90 causes client protein degradation via the ubiquitin—proteasome pathway, and is a mechanism that might simultaneously downregulate several redundant pathways crucial for cell viability and tumour development. HSP90 inhibitors are currently being developed as anticancer agents, and have shown early promising results in molecularly defined subgroups of solid tumours (eg, ALK-rearranged non-small-cell lung cancer and HER2-amplified breast cancer) and some haematological malignancies (eg, multiple myeloma).”

Metabolic Stress Regulates Cytoskeletal Dynamics and Metastasis of Cancer Cells

We show that tumors maintain energy production under nutrient deprivation through the function of HSP90 chaperones compartmentalized in mitochondria. Mitochondrial HSP90 proteins, including tumor necrosis factor receptor–associated protein-1 (TRAP-1), dampen the activation of the nutrient-sensing AMPK and its substrate UNC-51–like kinase (ULK1), preserve cytoskeletal dynamics, and release the cell motility effector focal adhesion kinase (FAK) from inhibition by the autophagy initiator FIP200. This results in enhanced tumor cell invasion in low nutrients and metastatic dissemination to bone or liver in disease models in mice. Phosphorylated ULK1 levels were correlated with shortened overall survival in patients with non–small cell lung cancer.

New Cancer Drug Ganetespib May Extend Survival in Late-Stage Lung Cancer

The new cancer treatment ganetespib produced encouraging results in a phase II/III clinical trial examining its effectiveness on late-stage lung adenocarcinoma, a form of non-small cell lung cancer (NSCLC). Patients received ganetespib in combination with docetaxel (Taxotere) or Taxotere alone. Ganetespib treatment resulted in longer overall survival (9.8 months compared to 7.4 months in Taxotere-only patients). Ganetespib inhibits a protein called Hsp90 that acts as a so-called molecular chaperone: it helps different proteins assume their final shape, thus allowing them to function. Many proteins ‘chaperoned’ by Hsp90 can drive tumor growth in cancer. Researchers hope that blocking Hsp90 with ganetespib will be effective even in patients who have developed mutations that make them resistant to other anticancer drugs, because even the mutated proteins likely still need Hsp90 to function. An ongoing phase III clinical trial seeks to confirm these results.