Cancer Drug Gamitrinib Weakens Tumor Defenses and Support Networks, Wistar Scientists Say

Cancer Drug Gamitrinib Weakens Tumor Defenses and Support Networks, Wistar Scientists Say

September 26, 2012

Gamitrinib Targets Tumor Mitochondria, Making Cancers More Vulnerable to Complementary Therapeutics

PHILADELPHIA – (September 26, 2012) – In almost every variety of cancer, mitochondria—the energy-producing structures within our cells—go into overdrive, supplying power to out-of-control cells and suppressing the natural mechanisms that halt growth. According to a team of researchers led by Dario C. Altieri, M.D., of The Wistar Institute, targeting tumor mitochondria could be the basis for new drugs that would apply to a wide variety of tumors.

Altieri and his colleagues have developed one such targeted therapeutic called Gamitrinib, which knocks out HSP90 (heat shock protein 90), an enzyme that is generally known to help damaged proteins fold back into their proper shape, as a type of emergency restorative protein origami. HSP90 appears abundantly in tumor mitochondria and maintains the ability in cancer of tumors to create chemical energy. In previous studies, Altieri demonstrated how Gamitrinib sensitizes glioblastoma tumors, making them more vulnerable to drugs that then trigger cell suicide.

“Tumors are terribly successful in adapting to changes in their local environments, which allows them to survive almost any type of drug, chemotherapy or radiation therapy that we throw at them,” said Altieri, the Robert and Penny Fox Distinguished Professor at Wistar and director of The Wistar Institute Cancer Center. “We found that HSP90 is a central component in the natural ability of cells to respond to stress, an ability that tumor cells take advantage of in their survival.

“By targeting HSP90 with Gamitrinib, we can take away this important survival network, making the tumor more vulnerable to combined treatments with other therapies,” Altieri said.

In the September 11 edition of the journal Cancer Cell, the Wistar scientists and their colleagues use Gamitrinib as a probe to test how HSP90 functions in tumor mitochondria. Their findings reveal that HSP90 is at the heart of a network of chemical pathways that allow cells to adapt to stress and environmental changes within the surrounding tissue. Tumors, they have shown, exploit this signaling network to promote their own survival and metastasize.

In introductory science textbooks, mitochondria are almost always first described as the energy “powerhouses” of cells. However, they also help cells cope with stress and damage and, failing that, push damaged cells toward self-destruction. According to Altieri, tumors have evolved a mechanism, hinging on HSP90, to generate more energy and bypass the mechanisms of cell self-destruction.

Mitochondria get their “powerhouse” tag because they are the structures within cells that help convert the energy in sugars into a more useful chemical form called ATP. This chemical energy, ATP, is then used to power chemical reactions in every type of cell. In their study, the researchers demonstrated how Gamitrinib, by inhibiting HSP90, blocked the production of ATP in cells grown from a variety of different cancers. 

In addition, HSP90 also prevents tumors cells from committing to a course of apoptosis--a system of programmed cell death by which diseased cells self-destruct for the greater good of the organism. If a cell accrues enough damage, as cancer cells do, a protein called CypD creates pores in the membrane that surrounds mitochondria, causing it to tear apart and leading to a host of self-destruct mechanisms within the cell itself. HSP90 re-folds CypD into a shape that does not allow for it to poke holes in mitochondrial membranes. In tumors, this allows cancerous cells to continue to grow and divide despite the molecular safeguards that have evolved to prevent this aberrant growth.

According to Altieri, the potential of Gamitrinib to lower the defenses of tumors could help boost the effectiveness of an emerging array of targeted therapeutics, drugs that are designed to attack specific cancer cells. These drugs are often successful initially, killing a great number of cancer cells in patients with advanced forms of cancer. However, the remaining cancer cells almost always develop resistance to the drug. A combination approach, Altieri believes, will prevent drug resistance from occurring.

“Our next step is to further develop the Gamitrinib compound, and begin evaluating toxicity, pharmacokinetics, and other drug - like properties,” Altieri said. “We already have some important evidence for strong synergy between Gamitrinib and other anticancer agents suggesting suitability for combination regimens.”

Funding for this project was through the National Institutes of Health’s National Cancer Institute.

Wistar co-authors of this study include Young Chan Chae, Ph.D., M. Cecilia Caino, Ph.D., Sofia Lisanti, Jagadash C. Ghosh,  Ph.D., Valentina Vaira, Ph.D., and Takehiko Dohi, of the Altieri laboratory, and Professor Meenhard Herlyn,  D.V.M., D.Sc. and Assisstant Professor, Jessie Villanueva, Ph.D. of Wistar’s Melanoma Research Center. Collaborating authors also include Nika N. Danial, Ph.D., of the Dana-Farber Cancer Institute of Harvard University; Stefano Ferrero, M.D., Luigi Santambrogio, M.D., and Silvano Bosari, M.D., of the University of Milan; and Lucia R. Languino, Ph.D., of the Kimmel Cancer Center of Thomas Jefferson University.

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today’s Discoveries – Tomorrow’s Cures. On the web at www.wistar.org.

FOR IMMEDIATE RELEASE:  September 26, 2012                                                     

Contact: Greg Lester, 215-898-3943