To prepare a potential new prostate cancer drug, called Gamitrinib, for trial in humans, The Wistar Institute has received a $1.5 million grant from the US Department of Defense's Congressionally Directed Medical Research Program.
The three-year grant will cover the costs of developing the data necessary to allow the use of Gamitrinib in the clinic. The end goal is to be able to file an Investigational New Drug application with the US Food and Drug Administration, says the drug's inventor and the project's lead investigator, Dario C. Altieri, M.D.
"Years of research have brought us to the point where Gamitrinib is ready for prime time," said Altieri, Wistar's Chief Scientific Officer and director of Wistar's National Cancer Institute-designated Cancer Center. "These funds will help us bridge the gap between a promising discovery and a practical drug for metastatic prostate cancer."
Metastatic prostate cancer remains a devastating disease in need of new therapies, says Altieri. According to the American Cancer Society, prostate cancer will kill about 25,000 Americans each year. "While there have been new prostate cancer drugs in recent years, their success is often measured in prolonging the lives of patients with metastatic disease for weeks or months," Altieri said. "We are interested in adding years to patients' lives—we want cures."
The Altieri laboratory designed Gamitrinib to disable multiple functions of mitochondria in cancer cells, prompting these cells to die. Gamitrinib was also shown to enhance the activity of other targeted cancer therapies in mice. The project began as the Altieri lab explored the role of a molecule called HSP90 in cancers. In particular, a body of evidence suggested that HSP90 accumulated in large amounts in the mitochondria of cancer cells. Mitochondria are organelles—structures within a cell—that help create useful energy for the cell and keep them alive.
While anti-HSP90 drugs exist, and are currently in the clinic, they have limited activity in cancer patients. This may reflect their inability to inhibit HSP90 in mitochondria, which are protected by their own membrane. Using combinatorial chemistry, Altieri and his colleagues created a molecule that would both target HSP90 and accumulate in mitochondria.
"Gamitrinib is, essentially, a two-piece molecule, one part drives it into mitochondria and the other inhibits HSP90," said Altieri. "This became a promising drug concept, one that might apply to multiple forms of advanced cancer, because only cancer cells seem to exploit mitochondrial HSP90 in relevant amounts."
Gamitrinib exploits a critical weakness of cancer cells. While mitochondria control energy production, they also control the inherent self-destruct mechanism within cells, a process called programmed cell death or apoptosis. It is a mechanism that is relevant to many forms of metastatic cancer, and Altieri believes that, in time, the drug will be used to treat many cancers in addition to prostate cancer. Over years of study, the Altieri laboratory has demonstrated how Gamitrinib can prime cancer cell mitochondria for destruction in cell cultures and animal models for many advanced forms of cancer.
The Department of Defense grant will enable the Altieri laboratory to make the final leap between laboratory science and trials in human subjects. The funds will allow Wistar to contract with third-party research organizations to conduct the formulation, toxicology, and pharmacology studies to demonstrate the drug's effectiveness and safety in anticipation of human trials. The funds will also support the development of a suitable biomarker—a biological signature that could be measured in patients to demonstrate the effectiveness of Gamitrinib-based therapy.
"In our studies we have shown the mechanism by which Gamitrinib works and potential drug combinations that will kill metastatic prostate cancer cells more effectively," Altieri said. "We are very excited and appreciative that the Congressionally Directed Medical Research Program has chosen our project for funding."
"We have cured a lot of mice, but now we hope to provide new therapeutic options to patients with advanced prostate cancer" Altieri said.