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.”


New Chaperone-Targeting Ganetespib Prolongs Survival in Advanced Lung Cancer

Adding the novel heat shock protein (HSP)-90 inhibitor ganetespib to docetaxel in salvage therapy is associated with prolonged overall survival (OS) compared to docetaxel alone among patients diagnosed with advanced adenocarcinoma lung cancer, report authors of the large randomized, first-in-class phase 2 GALAXY-1 clinical trial, presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting.”


NMS-E973, a Novel Synthetic Inhibitor of Hsp90 with Activity in Models of Drug Resistance to Targeted Agents, Including Intracranial Metastases

“Recent developments of second generation Hsp90 inhibitors suggested a potential for development of this class of molecules also in tumors that have become resistant to molecular targeted agents. Disease progression is often due to brain metastases, sometimes related to insufficient drug concentrations within the brain. Our objective was to identify and characterize a novel inhibitor of Hsp90 able to cross the blood-brain barrier (BBB)…”


Hsp90 Inhibitor Ganetespib Overcomes Resistance and Packs a Punch against ALK+ Tumors


A new drug has shown promising efficacy in non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) gene mutation. Ganetespib overcame acquired resistance to the drug crizotinib and showed strong antitumor activity in mice. Ganetespib works by inhibiting a “chaperone” protein called Hsp90 and thus targets multiple cancer signaling pathways for a more complete and lasting effect. Continue reading…


Inhibition of Wee1, AKT and CDK4 underlies the efficacy of the HSP90 inhibitor XL888 in an in vivo model of NRAS mutant melanoma

The HSP90 inhibitor XL888 is effective at reversing BRAF inhibitor resistance in melanoma, including that mediated through acquired NRAS mutations. The present study has investigated the mechanism of action of XL888 in NRAS mutant melanoma. Treatment of NRAS mutant melanoma cell lines with XL888 led to an inhibition of growth, G2/M phase cell cycle arrest and the inhibition of cell survival in 3D spheroid and colony formation assays…”