As part of the Faculty Salon Talks organized by HNU’s Office of Advancement, Tsze Tsang, PhD, assistant professor of chemistry, delivered a lecture in the Cushing Library on Thursday, April 13, about his work on the development of the compound cobimetinib (brand name Cotellic), which is used for the treatment of advanced melanoma. Tsang also gave a brief overview of the current state of cancer treatments and discussed the difficulties involved in creating new pharmaceuticals.
At the start of his lecture, Tsang provided a short background on different types of cancers, the factors that contribute to the development of cancer, and the various treatment strategies that are currently available.
“Cancer is kind of a misnomer,” he said. “It sounds like it’s one disease, but there are over 200 types of cancer and they all have very different biological and biochemical foundations. We can categorize them by cell origin, the cell they originated from—for example, sarcomas are from the bone, leukemia of course is from blood, lymphoma comes from a lymph node.
“And even within a specific type of cancer, we can have different underlying causes. There are things like radiation—UV light from the sun, which can cause skin cancer, x-rays, or radon gas, which is radioactive. Viruses can cause cancer. The Hepatitis C virus can cause liver cancer. The HPV (human papillomavirus) virus can cause cervical cancer. And there are environmental issues that are clearly well documented. Smoking, of course, is a big cause of lung cancer. Polycyclic aromatic hydrocarbons too—which is incomplete combustion of organic matter, like smoke from grilling meat, or from fires, or exhaust—can cause cancer. And, finally, genetics can be a source of cancer. Some people are more prone to have a certain type of cancer. A switch happens in one of their genes, from a stressor like the ones we discussed, and then that gene turns the cell into a cancerous cell.”
Tsang reviewed current cancer treatment strategies and spoke about how the use of each one depends on the patient and the type of cancer being treated. He explained how early detection, surgery, targeted radiation, chemotherapy, medication, and immunotherapy can be used to help patients recover from cancer.
During Tsang’s time working as a senior scientist at Exilixis, a biotechnology company in South San Francisco, he and other team members were engaged in new cancer drugs discovery. One of their goals was to develop a drug that could be used for the treatment of advanced (stage four) melanoma, which often cannot be treated with surgery, radiation, or chemotherapy. Tsang explained that many melanoma cells have a mutated BRAF gene that causes melanoma cells to grow and divide at a high rate, and that one of the drugs that exists to treat advanced melanoma, vemurafenib (brand name Zelboraf), works to disrupt the proteins in melanoma cells that initiate cell division. One of the goals for Tsang and his colleagues was to develop a drug that would work in a similar method, by disrupting the pathways that initiated cell division in cancer cells. Tsang also mentioned that he and his team wanted to create a drug that was more effective than a compound that the pharmaceutical company Parke-Davis had developed years earlier. During lab tests, the Parke-Davis compound was shown to be extremely effective in killing cancer cells, but when tested in living animal subjects like mice, it produced a high level of toxicity, and so it never became an approved drug.
After many different attempts to synthesize a compound that would be effective, Tsang and his team finally created one that they thought might be suitable. “When we tested it, we saw that it was more than four times as potent as the gold standard [the Parke-Davis compound],” Tsang said. “So we had our platinum standard with this new compound. It really was a tremendous result.”
As Tsang explained, despite the initial success, there was still much research that had to be done before the compound could become a drug. Tsang stated that there were acute toxicity screens (using mice) that had to be done on cobimetinib before it could move to clinical trials. Fortunately, the compound did not produce toxicity, and so advanced into full clinical trials, where it went through three stages of testing: stage one to establish safe dosage; stage two to determine the efficacy of the drug; and stage three to compare the new treatment to the current standard of care.
Cobimetinib successfully passed the clinical trials and, in November 2015, the U.S. Food and Drug Administration announced its approval of the drug for use in the treatment of advanced melanoma.
At the end of his lecture, Tsang mentioned that there are new clinical trials that are studying the use of cobimetinib in combination with other drugs—one for the treatment of colorectal cancer and another for the treatment of triple-negative breast cancer. “So that is the ongoing story of cobimetinib,” Tsang said.
Tsang acknowledged his colleagues from Exilixis and Genentech and expressed his gratitude to them at the end of his lecture. “I want to thank all the great scientists I worked with—all of us did the discovery work. And I want to thank Genentech for their work on the development and clinical trials.”