Exelixis announces cabozantinib preclinical data on pancreatic cancer

Feb 26 2012

Exelixis, Inc. (NASDAQ:EXEL) today announced the company's lead compound, cabozantinib, is highlighted in a new peer-reviewed publication demonstrating that simultaneous inhibition of MET and VEGF signaling reduces tumor invasiveness and metastasis in preclinical models of pancreatic cancer. The research, led by Dr. Donald M. McDonald at the University of California, San Francisco (UCSF), showed that selective inhibition of VEGF signaling with a neutralizing antibody against VEGF or with a small molecule kinase inhibitor resulted in more invasive and metastatic tumors than from placebo-treated mice. Importantly, this effect was accompanied by increased expression of MET. The researchers went on to show that treatment with cabozantinib (which targets both MET and VEGF signaling), or with a combination of selective inhibitors targeting both pathways, reduced these malignant processes. The researchers also reported that cabozantinib prolonged survival compared with all other treatment combinations examined.

The preclinical data will be published in the March 1, 2012 issue of Cancer Discovery and are also discussed in a press release issued by the American Association for Cancer Research, the journal's publisher. Starting today, the article will be available at http://cancerdiscovery.aacrjournals.org. Researchers at Exelixis collaborated on the studies with UCSF.

"These data provide important insights into the potential clinical benefits of simultaneously inhibiting the MET and VEGF signaling pathways with cabozantinib, and add to the scientific rationale for our ongoing clinical investigation of the compound," said Michael M. Morrissey, Ph.D., president and chief executive officer at Exelixis. "To date, cabozantinib has shown activity in 12 of 13 tumor types studied, including particularly encouraging interim results in castration-resistant prostate, medullary thyroid, renal, liver, ovarian, non-small cell lung, and breast cancers, as well as melanoma. These results suggest that, in many types of tumors, cabozantinib may have a potentially differentiated activity profile as compared to compounds that inhibit only VEGF or MET."

In the research described in Cancer Discovery, tumor-bearing mice were treated with an anti-VEGF antibody or with sunitinib, which inhibits multiple tyrosine kinases including VEGF receptors. These treatments were tested alone or in combination with an inhibitor of MET. Separate groups of animals were treated with cabozantinib. Key findings include:

• Cabozantinib reduced tumor invasiveness compared with VEGF inhibition alone, through a mechanism consistent with MET inhibition.
• Liver metastases were completely absent in animals treated with cabozantinib.
• Overall survival was longest in cabozantinib-treated animals. All animals treated with cabozantinib survived until the end of the study, whereas most or all animals in all other treatment groups did not survive until the end of the study.

"Inhibition of VEGF signaling has become a mainstay of cancer therapy, and its ability to delay disease progression and prolong survival in certain cancers has been extensively documented. However, there is a growing body of evidence suggesting that VEGF inhibition on its own can lead to increased tumor aggressiveness in some preclinical models and in at least one human cancer," said Donald M. McDonald, M.D., Ph.D., a member of the Helen Diller Comprehensive Cancer Center and the Cardiovascular Research Institute and professor of anatomy at UCSF. "These new preclinical findings suggest that upregulation of MET contributes to the evasive response of tumors to anti-VEGF therapy, and that simultaneous inhibition of MET and VEGF signaling can confer the benefits associated with VEGF inhibition while significantly reducing, and in some cases reversing, invasion and metastasis. Additional preclinical and clinical evaluation of combined MET and VEGF inhibition are clearly warranted."

Source: Exelixis, Inc.