Ganetespib shows potency against ALK-positive lung cancer and overcomes crizotinib resistance

Public release date: 26-Mar-2013
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Contact: Jeremy Moore
jeremy.moore@aacr.org
215-446-7109
American Association for Cancer Research

PHILADELPHIA A drug that indirectly impairs the function of several cancer-driving proteins, including anaplastic lymphoma kinase (ALK), may be an effective new treatment for patients with ALK--positive non-small cell lung cancer.

The drug, ganetespib, may also be effective for treating patients who have become resistant to the only FDA-approved targeted therapy for this disease, crizotinib, according to data published in Cancer 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 ALK protein typically respond well to crizotinib, which blocks that activity of the modified ALK and consequently kills off the cancer cells," said Proia. "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). Ganetespib targets heat shock protein 90 (Hsp90), a chaperone for many different proteins, including ALK, to ensure proper functioning. 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.

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.

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.

"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," said Proia.

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Follow the AACR on Twitter: @aacr

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About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www.AACR.org.

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Public release date: 26-Mar-2013
[ | E-mail | Share ]

Contact: Jeremy Moore
jeremy.moore@aacr.org
215-446-7109
American Association for Cancer Research

PHILADELPHIA A drug that indirectly impairs the function of several cancer-driving proteins, including anaplastic lymphoma kinase (ALK), may be an effective new treatment for patients with ALK--positive non-small cell lung cancer.

The drug, ganetespib, may also be effective for treating patients who have become resistant to the only FDA-approved targeted therapy for this disease, crizotinib, according to data published in Cancer 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 ALK protein typically respond well to crizotinib, which blocks that activity of the modified ALK and consequently kills off the cancer cells," said Proia. "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). Ganetespib targets heat shock protein 90 (Hsp90), a chaperone for many different proteins, including ALK, to ensure proper functioning. 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.

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.

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.

"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," said Proia.

###

Follow the AACR on Twitter: @aacr

Follow the AACR on Facebook: http://www.facebook.com/aacr.org

About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www.AACR.org.

---

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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

Source: http://www.eurekalert.org/pub_releases/2013-03/aafc-gsp031913.php

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