Posts Tagged → lung cancer
The American Society of Clinical Oncology (ASCO) meeting, held in Chicago earlier this month, brought some fascinating presentations on progress in two very tough to treat cancer types, lung cancer and advanced melanoma. This week, we’ll take a look at some of the data that emerged out of ASCO on small molecules that could overcome the limitations of existing therapies.
Treatment for lung cancer and melanoma has commonalities. Small molecule kinase inhibitors targeting a particular aberration driving the tumor have been approved for both types of cancer. But in each case, tumors eventually develop resistance to those kinase inhibitors, usually after about 6 to 9 months of treatment. Researchers are now trying to pinpoint the mechanism that tumor cells use to overcome the activity of kinase inhibitors, and then design new compounds or combinations of drugs that can improve patient outcomes.
Today we’ll focus on advances in non-small cell lung cancer (NSCLC). ASCO brought data from several new agents—most notably, Boehringer Ingelheim’s afatinib, AstraZeneca’s selumetinib, and Novartis’ LDK378—as well as new combinations of existing drugs.
First, some background on the current treatment paradigm in NSCLC: To date, scientists have identified several key protein receptors—EGFR, KRAS, and ALK—as drivers of the disease. Patients with a mutation in EGFR can take Genentech’s Tarceva (erlotinib) or AstraZeneca’s Iressa (gefitinib), but only after undergoing four cycles of chemotherapy. Although Tarceva was approved based on its ability to shrink tumors, it only prolongs survival in NSCLC patients by one month (12 months Tarceva vs. 11 months for placebo). Meanwhile, people who have the anaplastic lymphoma kinase (ALK-ELM4) translocation, can receive Pfizer’s Xalkori (crizotinib), which was approved in the U.S. in 2011.
Unfortunately, people with the KRAS mutation, which is considered mutually exclusive with EGFR, do not benefit from either additional chemotherapy or EGFR inhibitors. New therapies are desperately needed, since prognosis tends to be rather poor.
At ASCO this year, clinicians reported new data that answered some key questions about how best to treat people with these particular mutations: Continue reading →
FDA has given the regulatory nod to crizotinib, Pfizer’s ALK inhibitor that has proven very effective in the small portion of the population whose lung cancer is driven by the protein.
Pfizer says the drug, to be sold under the brand name Xalkori, will cost $9,600 per month, and it will provide assistance so that patient co-pays will not exceed $100. It’s the first in a handful of new drugs Pfizer is counting on to help offset the sales drain when the patent expires this fall on its blockbuster cholesterol drug Lipitor.
The approval is notable as the second drug/diagnostic combo to get the FDA green light in recent weeks—Plexxikon/Roche’s melanoma treatment Zelboraf is the other.
Also notable? We call the compound an ALK-inhibitor, but scientists didn’t start out looking for an ALK-inhibitor. Work on crizotinib originated at Sugen, a South San Francisco-based biotech first bought by Pharmacia, which was later acquired by Pfizer. Sugen chemists were intent on finding a molecule that blocked c-Met, a protein implicated in tumor metastasis. They had already struck upon a promising amino pyridine scaffold by the time their activities were moved into Pfizer’s La Jolla site, where lead optimization took place.
An optimized molecule, billed as a c-Met inhibitor, was put into clinical trials. Then, as we wrote last year, scientific discovery and serendipity converged to change the course of the drug’s development:
Researchers led by Hiroyuki Mano, a professor of functional genomics at Japan’s Jichi Medical University, found that when a certain chromosome inverted, a fusion occurred in lung cancer cells between the echinoderm microtubule-associated proteinlike 4 (EML4) gene and the ALK gene. The researchers found that the fusion caused tumor formation in mice. A subsequent test determined that about 7% of lung cancer patients had this fusion gene. In a paper published in Nature, the researchers concluded that ALK would make a good drug target (Nature 2007, 448, 561).
As it happened, Pfizer had just learned it had an ALK inhibitor on its hands. The company and Massachusetts General Hospital had evaluated results from large biochemical and cell-based screens to see whether crizotinib was hitting targets other than c-Met, says James Christensen, director of translational research in Pfizer’s oncology unit. Upon characterizing the hits, the collaborators found that it was blocking ALK’s activity.
Better, crizotinib was just as good at blocking ALK as it was at shutting down c-Met. Pfizer scientists believe the dual activity is due to a similarity in a residue on each protein. Specifically, both c-Met and ALK have a particular tyrosine within one of the three phosphorylation sites, called the activation loop, which seems to be responsible for the compound’s activity.
All in all, pretty cool science that has translated into a very promising treatment for some lung cancer patients.
The American Society of Clinical Oncology (ASCO) meeting in Chicago has been dominating pharma news for the past few days. And while much of the cancer-drug-related news coming out of the meeting is about biologics, the small molecule crizotinib is in the spotlight, too. Crizotinib is an experimental drug that Pfizer is developing for the treatment of lung cancer in a very specific set of patients.
Much of the crizotinib coverage focuses on its targeting of anaplastic lymphoma kinase. While many “targeted” drugs have reached the market in recent years, very few types of cancer are driven by a single genetic mutation, so the drugs’ effect has therefore been limited. One of the rare exceptions is Novartis’ drug Gleevec, which targets a protein kinase called BCR-ABL. Gleevec has been called a miracle drug for its ability to halt a rare type of leukemia; some scientists now think crizotinib could be another of those rare exceptions. Robert Langreth at Forbes quotes Mark Kris, a scientist at Memorial Sloan-Kettering Cancer Center, who likens crizotinib to Gleevec.
While it’s too early to compare an experimental therapy like crizotinib to Gleevec, a successful marketed drug that has had a major impact on cancer research, at a molecular level, Kris is right, since both drugs do go after kinases.
Crizotinib is designed to work on the ~3-5% of lung cancer patients with an alteration in the ALK gene- that’s roughly 10,000 people in the USA, according to the Wall Street Journal. WSJ has articles on crizotinib here and here.
Now, when I see the word kinase, the first place I hunt for information are the archives of KinasePro. That didn’t disappoint- and revealed some more details of the drug’s story.
According to a discussion on KinasePro, the patent literature reveals that the series of compounds that included the future crizotinib was discovered by scientists at Sugen, a company which Pfizer acquired. We alluded to the fact that Pfizer inherited many such molecules in our coverage of drugs targeting Met, a tyrosine-kinase receptor implicated in many cancers. As the WSJ noted, crizotinib’s activity against Met, which was the reason Pfizer acquired it in the first place, has so far turned out to be less important than its effects on ALK. It’s worth noting that Gleevec targets other kinases as well- it’s not perfectly selective for BCR-ABL.
Is there a lesson for cancer research in here? Is high selectivity for one molecular target necessarily a good thing in drug development?
Bonus: If you want to get a real feel for the ‘needle in the haystack’ exercise that pharma is, try downloading the 2004 patent that KinasePro cites as the earliest mention of the series. It’s 300 pages long and packed with compounds, most of which will never get anywhere near a person, let alone a pharmacy shelf.