Specific Targeting of Tumor Cell Survival through Blockade of Hsp90 and Survivin Interaction

Abstract

Researchers at the University of Massachusetts Medical School and colleagues announced the development of a molecular anti-cancer agent, called shepherdin, that selectively kills tumor cells while sparing normal cells nearby, offering what may be a promising new approach to cancer therapy. Dario C. Altieri, MD, UMMS professor and chair of cancer biology and Director of the UMass Cancer Center (and member of the Editorial Board of Cancer Biology and Therapy), worked with colleagues in Italy and at the Moffitt Cancer Center in Florida to develop the compound, which was described in a study published in the May 2005 issue of the journal Cancer Cell.

"This is an exciting development in an area of great need," said Altieri, noting that traditional cancer treatments do not differentiate between cancerous and non-cancerous cells and thereby often cause extensive damage to healthy tissue. "We have learned so much about how cancer works and yet we have few targeted therapies for patients. This may be a very effective model through which therapeutic agents can seek out and destroy only the malfunctioning, cancerous cells, leaving normal, healthy cells unaffected."

In 1997, Altieri discovered the protein survivin, which is overabundant in cancer cells and protects the cells from death, allowing for unchecked proliferation and tumor growth. Based on his work with survivin and previous studies of another protein-heat shock protein 90 or Hsp90-which "chaperones" survivin to ensure its durability and its delivery into cells, Altieri sought a way to interfere with the function of these two particular proteins. He engineered a compound called shepherdin, which binds to Hsp90 and blocks its ability to work with survivin.

In human cancer cell cultures and in mice harboring human cancer types, shepherdin binds to Hsp90 and impairs survival mechanisms of tumor cells, resulting in massive destruction of tumor cells and substantial inhibition of tumor growth in mice. The anti-tumor activity of sherpherdin is selective in that normal tissues and organs are not affected, and prolonged use of shepherdin in mice is well tolerated with no signs of toxicity. Taken together, these features may make shepherdin an attractive drug for targeted cancer therapy.

Shepherdin qualifies as a new class of anti-tumor agent, capable of disrupting essential survival mechanisms in tumor cells but without compromising the function of normal tissues. In the recently published studies, shepherdin was active on a wide variety of types of cancers, regardless of their origin or genetic makeup. This makes shepherdin suitable for broad therapeutic applications in clinical oncology. The full clinical development of shepherdin is currently being actively pursued through the generation of advanced derivatives with more favorable chemistry for use in humans.

The University of Massachusetts Medical School, one of the fastest growing academic health centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research. The Medical School attracts more than $173 million in research funding annually, 80 percent of which comes from federal funding sources. For more information visit www.umassmed.edu

The UMMS Department of Cancer Biology, created in 2002, seeks to provide outstanding research contributions in all the fundamental mechanisms that lead to the onset, progression and dissemination of cancer. Faculty are dedicated to bridging basic science with translational cancer research to tangibly advance the fight to prevent, diagnose and treat cancer. For additional information, go to www.umassmed.edu/cancerbiology.