Transforming rearrangements of the ALK (anaplastic lymphoma kinase) gene define a unique subset of patients with non?small cell lung carcinoma (NSCLC). While ALK gene rearrangements affect only about 4% of all lung cancers, they are more frequent in adenocarcinomas, in never or light smokers, and seem almost mutually exclusive with activating EGFR or KRAS mutations. Today, the clinical success of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib (Xalkori? Pfizer), the only FDA-approved targeted therapy for this disease, in this patient population has become a paradigm for molecularly targeted therapy.

Ongoing clinical trials now show that a new drug, ganetespib (also known as STA9090), with the ability to indirectly impair the function of several cancer-driving proteins, including anaplastic lymphoma kinase, may be a more effective treatment for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC).

Ganetespib, as it turns out, may also be effective for treating patients who have become resistant to crizotinib, according to data published inCancer Discovery, a journal of the American Association for Cancer Research.

?Lung cancer, a leading cause of death, is no longer thought of as a single disease, but rather as a group of diseases, each with a distinct genetic profile,? according to David Proia, Ph.D., associate director of cancer biology at Synta Pharmaceuticals Corporation, the company that funded the research. ?This realization has paved the way for the design of new treatments tailored to the specific biological characteristics of a patient?s tumor.

?For example, patients with lung cancer caused by alterations in the anaplastic lymphoma kinase (ALK) protein typically respond well to crizotinib, which blocks that activity of the modified ALK and consequently kills off the cancer cells,? Proia explained. ?However, as is the case for many cancer drugs, most patients treated with crizotinib eventually become resistant to the drug.?Proia and colleagues investigated ganetespib as an alternative treatment for ALK-positive non-small cell lung cancer (NSCLC).

Function
Ganetespib is a potent, next-generation Heat Shock Protein 90 (Hsp90) inhibitor that is structurally unrelated to the first-generation ansamycin class of Hsp90 inhibitors.The trial drug is a molecular chaperone required for proper folding and activation of many different (cancer-promoting) proteins, including ALK. Hsp90 is generally recognized as a key facilitator of cancer cell growth and survival.However, when Hsp90 is blocked, ALK can no longer work properly and is destroyed by the cell. Once ALK is lost, the cancer cells die and the tumors shrink.

Greater Potency
Ganetespib had 30 times greater potency than crizotinib against a cultured ALK-positive NSCLC cell line, resulting in the complete loss of ALK protein expression. In addition, the drug was active against ALK-positive lung cancer cell lines that had become resistant to the effects of crizotinib.

Mouse models
The researchers then compared ganetespib and crizotinib in mice xenografted with human ALK-positive NSCLC cancer cells. Ganetespib displayed greater antitumor activity and prolonged animal survival as compared to crizotinib. It was also shown that ganetespib had meaningful activity in a patient with ALK-driven NSCLC who had responded to, and then progressed, following crizotinib therapy.

The researchers also noted that the combination of ganetespib with other targeted ALK agents both in vitro and in vivoresulted in synergistic antiproliferative effects in several human non-small cell lung carcinoma (NSCLC) tumor xenografts.And most importantly, ganetespib overcame multiple forms of crizotinib resistance, including secondary ALK mutations which are consistent with activity seen in a patient with crizotinib-resistant NSCLC.

Cancer cells driven by ALK amplification and oncogenic rearrangements of ROS1 and RET kinase genes were also sensitive to ganetespib exposure. Finally, clinical trial data from an open label phase II study presented at ASCI in 2011 shows that ganetespib administered as a single-agent is well-tolerated in patients with NSCLC at 200 mg/m2once weekly without severe liver, ocular, cardiovascular or renal toxicity.

?Ganetespib therapy represents a new option for treating ALK-dependent lung cancer in sequence with direct ALK inhibitors and/or for treating patients who relapse following direct ALK inhibitor therapy,? Proia noted.

For more information:
– Sang J, Acquaviva J, Friedland JF, Smith DL, Sequeira M, Zhang C, Jiang Q, et al. Targeted Inhibition of the Molecular Chaperone Hsp90 Overcomes ALK Inhibitor Resistance in Non?Small Cell Lung Cancer. Cancer Discovery; Published OnlineFirst March 26, 2013; doi: 10.1158/2159-8290.CD-12-0440
– Wong K, Koczywas M, Goldman JW, Paschold EH, Horn L, Lufkin JM, Blackman RK, Teofilovici F, Shapiro G, Socinski MA. An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC).J Clin Oncol May 2011; 29 (15) suppl 7500 (meeting Abstract)

Clinical trials
NCT01579994 – Crizotinib and STA-9090 in ALK Positive Lung Cancers
NCT01348126 – Study of Ganetespib (STA-9090) + Docetaxel in Advanced Non Small Cell Lung Cancer (GALAXY)
NCT01562015 – A Study of Ganetespib in Subjects With ALK-Positive Non-Small-Cell Lung Cancer (NSCLC) (CHIARA)
NCT01798485 – A Phase 3 Study of Ganetespib in Combination With Docetaxel Versus Docetaxel Alone in Patients With Advanced NSCLC (Galaxy 2)
NCT01590160 – Ganetespib With Pemetrexed-cisplatin, in Patients With Malignant Pleural Mesothelioma (MESO-02)
NCT01031225 – A Study of the HSP90 Inhibitor, STA-9090 in Subjects With Stage IIIB or IV Non-Small Cell Lung Cancer (NSCLC)
NCT01173523 – Study of Hsp90 Inhibitor, STA-9090 for Relapsed or Refractory Small Cell Lung Cancer

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