#ASCO12 Data Digest: Overcoming Resistance in Metastatic Melanoma
Jun29

#ASCO12 Data Digest: Overcoming Resistance in Metastatic Melanoma

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog. Not long ago, metastatic melanoma was considered a graveyard for clinical research. But last year brought a major breakthrough in treating skin cancer: the approval of Roche’s Zelboraf (vemurafenib), a small molecule that has proven highly effective at treating the roughly 50% of the patient population that carry the BRAFV600E mutation. However, Zelboraf has limitations. Patients’ disease eventually becomes resistant to the drug and the lesions caused by the skin cancer tend to return after 6 to 9 months. At the American Society of Clinical Oncology (ASCO) meeting earlier this month, the big two questions on cancer specialists’ minds were: what are the mechanisms of resistance and how can we develop strategies to overcome them? An amazing thing about current melanoma research is that several physician-scientists involved in the clinical trials are also actively involved in translational research--this is sadly the exception rather than the rule, in oncology. But the connection between basic science and bedside has meant new targets are being identified and quickly tested in the clinic. One potential target recently discovered was MEK, a kinase that sits along the same signaling pathway as BRAF. When BRAF activity is turned off by Zelboraf, cancer finds a way to compensate for the loss by exploiting other kinases in the pathway. Researchers think that by combining a BRAF inhibitor with a MEK inhibitor, the pathway might be more comprehensively shut down than by either alone. Consequently, there was a tremendous amount of buzz around a melanoma trial that looked at combining a BRAF inhibitor, GSK2118436 (dabrafenib), and a MEK 1/2 inhibitor, GSK1120212 (trametinib). Previous studies have shown that given alone, dabrafenib could result in solid response rates of 59%; trametinib, meanwhile, produced a 25% response rate when given as a single agent. Jeffrey Weber from Moffitt Cancer Center in Tampa presented the results of the complex phase I/II study, which included melanoma patients with either the BRAFV600 E or K mutation who had not undergone treatment of any kind. The hope was that by suppressing the MAP kinase-dependent resistance mechanisms, patients would enjoy three kinds of improvements over current treatment: 1) Improved progression-free survival (PFS), response rate, and survival 2) Prolonged duration of response 3) Decreased incidence of BRAFi-induced proliferative skin lesions An impressive waterfall plot of tumor shrinkage for patients (n=77) with the BRAFV600K mutation drew gasps from the audience - only four patients failed to respond to the combination, while the majority had a response of 30% or better. This isn't something you see every...

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The Right Kinase, Part II – Roche and Daiichi’s Vemurafenib Approved
Aug24

The Right Kinase, Part II – Roche and Daiichi’s Vemurafenib Approved

Last week, the FDA approved Zelboraf (vemurafenib), co-marketed by Roche and Daiichi Sankyo, for the treatment of melanoma characterized by genetic mutation BRAF V600E, which occurs in a subset of the overall patient population. Treatment of late-stage melanoma patients with Zelboraf increases their survival around five months longer than traditional chemotherapy. Cancer-stricken families believe this extra time justifies the $9400 / month price tag for the treatment, considering the dearth of treatments currently available for these near-terminal patients  (for a more detailed look into the people who brought vemurafenib to market, read Amy Harmon’s New York Times article series from 2010). Vemurafenib went from concept to approval in just six years, lightning-fast for pharma, which usually takes decades to bring a drug to market. So, what’s the secret behind its success? Vemurafenib, developed initially by San Francisco pharma company Plexxikon (acquired in 2011 by Daiichi Sankyo) shows all the hallmarks of rational drug design. Initial screening of a 20,000-member compound library against the ATP-binding site of 3 kinases (Pim-1, CSK, and p38) yielded a 7-azaindole lead structure. This approach, known as fragment-based lead discovery (FBLD) - the concept that a drug can be built up from a tiny piece as opposed to a high-potency binder -  may represent a first for the industry, as pointed out by Dan Erlanson of blog Practical Fragments. Further synthetic modification of this azaindole fragment, supported by computer binding studies, showed that a hydrophobic (nonpolar) pocket on the enzyme surface could best be filled by a difluoro-phenylsulfonamide group. Biochemical assays confirmed that a ketone linker (in place of the 3-aminophenyl group shown above) between the azaindole and the sulfonamide increased potency. Additionally, a 5-chloro residue on the azaindole eventually became a 4-chlorophenyl group; it’s unclear how this relatively non-polar group helps improve binding, since early active-site models suggest it faces out towards the watery cell cytoplasm. How is Zelboraf halting melanoma growth? It all comes down to kinase inhibition, a topic covered with both a story and a Haystack post here at C&EN last year. B-RAF, a common gene overexpressed in melanoma cells, produces a protein kinase that is selectively inhibited by Zelboraf. Once shut off, this pathway reinstates a “lost” negative feedback loop for the BRAF V600E tumor cells, resulting in a cascade failure of growth factors further down the line. Cell growth arrest or apoptosis (cell death) follows, but only for the targeted melanoma cells, with no effect on non-cancerous cells. In an interesting twist, a review published in July shows that inhibitors of Raf kinases (the family of kinases that includes the product of the B-RAF gene) can be developed for...

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The Right Kinase
Sep09

The Right Kinase

Today I posted a news story about the debut of the structure of PLX4032, a promising melanoma drug developed by Berkeley, California startup Plexxikon. This drug's story has already been given the narrative treatment courtesy of the New York Times. And when the results of a Phase I clinical trial of PLX4032 came out, it got covered in many other news outlets as well. But we here at The Haystack are most interested in PLX4032's chemical backstory. And when I contacted kinase expert Kevan M. Shokat for his opinion on the work, he said the story has another dimension- clues about how to pick the right kinase targets to treat diseases. The kinase enzyme that Plexxikon's experimental drug targets is called B-RAF. It's part of a critical signaling pathway that also includes the kinases MEK and ERK. What's interesting about Plexxikon's stunningly successful early trial (81% of patients taking PLX4032 saw their tumors shrink) is just how well people tolerate the drug, Shokat says. The patients in that 81% success group were taking almost a gram of the stuff, twice daily. This is despite the obvious central importance of the RAF-MEK-ERK pathway, and in contrast to what happens when you block MEK, just one step down the pathway, Shokat says. Compounds that block MEK tend to have what's called a narrow therapeutic index- there's a small window between giving an effective dose and giving a toxic one, he says. So if researchers could understand why such a dramatic difference exists, it could help them make the right kinase choices for other diseases as well, he says. When I spoke with Plexxikon's senior VP of research, Gideon Bollag, he too had interesting things to say about kinases, but our discussion was less about choosing one kinase out of many and more about making the commitment to choosing one at all. "Over the last 10 years or so many of the drugs for cancer have been multitargeted kinase inhibitors, and I think our compound is changing that paradigm," he says. "More selective compounds can be more effective because you can dose higher levels safely," he...

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