Many readers will have noticed that the advanced prostate cancer market is rapidly becoming crowded with three new therapies (cabazitaxel, sipuleucel-T and abiraterone) already approved and several more in late stage development, including Alpharadin (radium-223) and MDV3100, both likely to file this year. In addition, others are focused on bone complications, such as denosumab, which is expected to have a tough ODAC meeting this month, and cabozantinib, a multikinase inhibitor currently in phase III trials.
This weekend heralds the annual American Society of Clinical Oncology (ASCO) Genitourinary (GU) meeting in San Francisco, although ASCO held their press briefing today to provide an update on some of the key topics.
For those of you interested in Alpharadin (radium-225) in castrate-resistant prostate cancer (CRPC), check out the update of Dr Oliver Sartor’s presentation, which is covered on Biotech Strategy Blog.
The key topic that most interested me though, was Dr Howard Scher’s update on Medivation’s Androgen Receptor antagonist, MDV3100, in CRPC. Previously, Medivation announced that the data showed an improvement in median overall survival (OS) of 4.8 months and this is still solid (Note: J&J’s abiraterone was approved by the FDA based on an OS of 3.9 months in the same population and must be taken with prednisone).
Pancreatic cancer as many readers know, is one of those cancers that is generally diagnosed later than most in stage IV and as a result, has a poor prognosis, often only a year or so from diagnosis.
It has been known for a decade that constitutive Kras and NF-kB activation is one of the signature changes in the disease in the majority (80-95% ) of patients. Kras is a particularly important gene because it is often involved with on-off signaling of other genes. In addition, mutational inactivation of a key tumour suppressor gene (Ink4a/Arf) also occurs in over half (50-75%) of pancreatic adenocarcinomas. What is not known, however, is what are the key signaling pathways downstream of Kras and how they relate to pancreatic cancer.
There’s been quite a flurry of commercial news on the Pharma front this morning, with Amgen buying Micromet (whose leading product is blinatumumab in ALL) and Celgene announcing their acquisition of Avila Therapeutics who have a Bruton Kinase Inhibitor (BTK) AVL-292 in phase IB development for lymphomas, which was all the rage at the recent American Society of Hematology (ASH) meeting last month.
The big news for me today, though, wasn’t the commercial acquisitions but a gem of a paper relating to science and its significance for future cancer treatment.
After a number of basic research and science sessions over the last two days (see the Update 1 post on the science that intrigued me for more details), but the last two days heralded some excellent clinical sessions, in both oral and poster forms. These included the presentation of the much anticipated update to the BOLERO-2 trial, which was also published in the New England Journal of Medicine online and the CLEOPATRA study, also published in the same journal. One of the more impressive posters that caught my eye was the ENCORE 301 study, which provided an update to the entinostat data in ER/PR+ HER2- advanced breast cancer.
Yesterday evening brought a flurry of news around the New England Journal of Medicine articles for the BOLERO2 and CLEOPATRA trials, but out of respect to the presenters, I hate talking about the actual data before its being presented. Call me old fashioned if you like, but it seems odd moving up deadlines for the publication ahead of the presentations instead of releasing them on the day and is a little disrespectful of the journal towards the presenter and attendees.
That was the quaint phrase used by one of the presenters at the recent AACR-EORTC-NCI Molecular Targets meeting in San Francisco.
Apparently, some drug or two was considered, too toxic (fair enough) or lacking in efficacy, hence the requisite binning of a multi-million dollar program to the scrapheap.
Yesterday’s post, however, reminded me that maybe sometimes, it’s not that the efficacy was lacking but the clinical trial design or tumor type or even line of therapy was the best one. Let’s consider a couple of recent ideas here:
A couple of articles in the latest Cancer Discovery looked at some rather promising, and perhaps a little unexpected, findings pertaining to epigenetic therapy.
What are epigenetics?
If you read up on epigenetics in the medical journals, you will come across some of the most dense and complex articles I’ve ever come across in cancer biology. That said, there are a few readable examples around such as Bird’s (2007) short insight piece in Nature.
“Scientists at Dalhousie University in Nova Scotia have identified a key mechanism of metastasis that could lead to blocking tumor growth if their findings are confirmed.”
Loved this opening to an AACR press release about a key paper (freely available for anyone to download – see the reference session below) that was just published in Cancer Research by David Waisman’s group.
Now, before getting into the technical details, I was reflecting recently on both my recent awesome trip to the MD Anderson basic research campus at Smithville, Austin where a lot of research into tumorigenesis is conducted and pointed questions from patients about why their hasn’t been enough progress in treating and curing metastatic breast cancer.
This morning I was reading a fascinating paper on lung cancer and one of my favourite proteins, CRKL, from the group of prolific lung researchers at Mass General, Dana Farber, MIT and the Broad Institute in Boston:
“Over-expression of CRKL in immortalized human airway epithelial cells promoted anchorage-independent growth and tumorigenicity. Oncogenic CRKL activates the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death.”
Cheung et al., (2011)
We also know that one of the mechanisms of resistance to gefitinib is over-expression of CRKL in EGFR-mutant cells by activating ERK and AKT signaling.