When thinking about a sports metaphor to describe the upcoming proceedings of the American Association of Cancer Research (April 6-10, Washington DC), we were reminded of football. No, not the European (and some would say, proper) kind, but American football. At this time of the year, aspiring college players undertake a week-long ritual known as the NFL Combine. Players assemble in Indianapolis (!) are a put through a grueling schedule of sprints, feats of strength, and agility tests that are specific to the position the player hopes to fill. Some of these are more preposterous than others, and seem to have been conceived by deranged reality TV script writers (is that redundant?). Based on their performance in such events as the 40-yard dash and bench press, their prospects may raise or fall for the NFL Draft in April.
Putting Novel Compounds Through Their Paces
So our thoughts turned to AACR and the similarities with the Combine; a parade of antibodies, small molecules, antisense oligos, siRNA constructs, vaccines, etc. The AACR is traditionally the proving ground for those agents that someday hope to make it to the plenary at ASCO; sticking with the football metaphor, this is like getting to the Super Bowl of oncology (or at least analogous to the conference championship). While the proceedings of AACR are rarely immediately impactful, many of the stars of today, such as ibrutinib, idelalisib, ipilimumab, vemurafenib, and palbociclib, were once nothing more than a poster presentation at AACR. While there are also many false positives that evidence themselves here, the prospecting can be very lucrative to the trained eye. In today’s favorable environment towards oncology, timelines can become highly compressed (INFI being one of the best examples of this) between the time a compound shows activity in the lab to the time clinical responses are being seen in patients.
Many of AACR 2012’s themes will repeat themselves at AACR 2013
A scan of the titles of the topical discussions and abstract titles suggests that many of the themes that played out last year will once again take the spotlight in 2013. One of our favorite topics is that of epigenetics, an area of near total “white space” in oncology research. An educational session on Saturday the 6th will feature topics germane to the entire space. In addition, the plenary session on Monday the 8th will be chaired by Robert Copeland, the CSO of Epizyme, one of the more successful development-stage companies in the space which is concentrating its firepower on histone methyltransferases (HMTs). Also featured will be a number of talks on histone deacetylase inhibitors (HDACs), an area that has yet to fulfill its true promise despite the approval of such agents as Zolinza and Istodax. We also will keep our eyes on further data to be presented by Astex (ASTX), which will provide an update on the clinical activity of SGI-110, a dinucleotide analog of decitabine (Dacogen) in patients with MDS and AML. While something of a new twist on an “old school” hypomethylating agent (HMA), SGI-110 appears to possess intriguing activity in these common conditions, and has show activity in patients who have been pre-treated with first-generation HMAs, Dacogen and Vidaza (azacitidine). Given the relationship to the essentiality of the cancer cell, the epigenetics space has the potential to be as large as or larger than that of kinase inhibitors.
Also big this year will be such topics as tumor cell metabolism, the molecular basis of the cancer stem cell and the EMT, the junction between “steminess” and the epithelium. Expect to hear more about targets such as FAK, Wnt, Notch 1/2 and hedgehog (this story still has more to go beyond Erivedge, in our view). Of course, AACR 2013 will contain the usual panoply of kinase inhibitors. Naturally, with the success of such compounds as idelalisib and IPI-145, a large number of putative contenders to greatness will show their stuff, ranging from the pan-PI3 kinase inhibitors, to combination PI3K/mTOR inhibitors, AKT/mTOR inhibitors, and MEK inhibitors. It truly is anyone’s guess a priori which amongst these will ultimately be successful, and human clinical data will ultimately sort the winners from the also-rans.
What the “eff” with FGF and IGF inhibitors?
While the F “Family”, namely VEGF and EGF, have yielded successful commercial products (though not always in line with early biologic hypotheses), the same cannot be said of the other members of the growth factor family, namely FGF (fibroblast growth factor) an IGF (insulin-like growth factor). We would throw PDGF (platelet-derived growth factor) onto that pile as well. Despite early expectations of clinical success with inhibitors of these factors, whether they be small molecule or large, receptor or ligand, positive clinical results have been fleeting. Perhaps this is because of the nature of the underlying biology whereby they play more of an accessory, rather than principal, role. In addition, the level of driver mutations and/or overexpression does not seem to have tracked that of VEGF and EGF. Despite the disappointment to date, this may be the year in which FGF (in its various forms) finally emerges as a validated drug target. Several presentations will speak to the biologic validity of the members of the FGF family. Taking them in numerical order, FGFR1 appears to play a key role in a variety of squamous cancer subtypes like SCLC, while FGFR2 may participate in the pathogenesis of breast, prostate and papillary renal cancer. FGF2 also is the subject of a presentation tying its role to the development of resistance to ABL kinase inhibitors in CML (good for Iclusig?). Finally, the link between mutations in FGFR3 and bladder cancer is once again discussed in a paper that describes the activation of FGFR3 to a genomic fusion product. Obviously, wherever a potential target exists, chemical matter will emerge to interact with it. Of interest to us will be a human antibody to FGFR2 IIIc from a company called Attogen Bio, as well as a handful of specific and less-specific (a/k/a “dirty”) kinase inhibitors such as AZD4547 and PD173074 in the former category, and dovitinib (can you believe it’s still alive?) and ponatinib (Iclusig). Definitely a space to watch, in our view. Happy prospecting!
by Mike King, Managing Director and Senior Biotechnology Analyst, JMP Securities
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