While early efforts to target phosphoinositide-3 kinase (PI3K) involved pan-inhibition, biotechs like Intellikine Inc. and Calistoga Pharmaceuticals Inc. differentiated themselves by selectively targeting the alpha, beta, delta and/or gamma isoforms of PI3K rather than hitting the whole family.
Their rationale was the same as with any targeted cancer drug: Narrowly focusing on just the right target should, theoretically, decrease side effects associated with off-target activity, facilitate combinations, and allow higher dosing to achieve better efficacy.
That theory resonated with big pharma and big biotech. In the last year, Gilead Sciences Inc. bought Calistoga, while Takeda Pharmaceutical Co. bought Intellikine, which had already inked a deal with Infinity Pharmaceuticals Inc. worth nearly $500 million. Exelixis Inc. also licensed its PI3K delta programs to Merck & Co. Inc. (See BioWorld Today, Feb. 28, 2011, and Dec. 22, 2011.)
Yet the answers in cancer are never straightforward, and the same is true with PI3K.
More or Less
"Talking to potential partners in large pharma, one of the most popular questions I received was, 'Do we need to be more selective or less selective?'" said Christian Rommel, Intellikine's chief scientific officer. "This question in oncology will not go away."
As Intellikine's isoform-selective program indicates, Rommel favors the more targeted approach. "I'm a true believer in: Know your target, go to your mutations, select your patients and hit the target very hard," he told BioWorld Insight.
As evidence he pointed to Zelboraf (vemurafenib, Daiichi Sankyo Co. Ltd. and Roche AG), which targets tumors carrying the BRAF V600E mutation. First generation pan-inhibition of RAF signaling hadn't worked, and Rommel noted that even highly-targeted Zelboraf did not initially generate strong responses until it was reformulated for higher potency.
Does that indicate highly targeted, highly potent cancer drugs are always better? Not necessarily.
Curis Inc. is best known for Hedgehog pathway inhibitor Erivedge (vismodegib), approved last month for advanced basal cell carcinoma. But earlier in its pipeline, Curis is working on a pan-PI3K/HDAC inhibitor called CUDC-907. (See BioWorld Today, Jan. 31, 2012.)
Why take the pan rather than isoform-selective route? Curis President and CEO Dan Passeri said he believes selective PI3K inhibitors have "limitations" in their ability to impact tumors with disregulation of other signaling pathways and thus will only have niche applications. He voiced concerns that other pathways would be able to work around the highly-targeted agents and create resistance.
In preclinical studies, CUDC-907 has shown anti-proliferation activity against cancer cell lines that are insensitive to single-target PI3K inhibitors, including solid tumors with K-RAS mutations. It has also shown anti-proliferation activity up to 100-fold more potent than two leading PI3K inhibitors in development, according to Curis.
Rommel lamented that "resistance will always come with molecular targeted therapies." Yet he argued that in the case of PI3K, resistance is "not top priority" because there are still so many other questions that need to be answered. "We need to clinically validate the oncogene first," he said. "Tell me first where it works and how good it works and then we'll talk resistance."
Kevan Shokat, professor at the University of California in San Francisco and a cofounder of Intellikine, agreed. "Before we worry about which particular variant is able to decrease the chance of drug resistant mutations, we should worry about getting some efficacy, which always comes with resistance unfortunately," he said.
Shokat also noted that pan-PI3K inhibitors might not be any less vulnerable to resistance than isoform-selective PI3K inhibitors. As evidence, he pointed to the fact that Gleevec (imatinib, Novartis AG), which is highly selective for the kinase BCR-ABL, falls victim to the T315I mutation. But Sprycel (dasatinib, Bristol-Myers Squibb Co.), which hits several kinases, also falls victim to the T315I mutation because one of the many kinases it hits is BCR-ABL.
Rommel has another thought on resistance: The best way to avoid resistance is to kill your tumor. And the best way to kill a tumor is to hit it as hard as you can, for as long as you can. And you can only do that if your drug is targeted.
Together or Separate
Hitting a tumor long and hard with a selective drug is only part of the answer, however. Most oncologists expect successful cancer treatment to follow in the footsteps of HIV and eventually involve cocktails of several targeted drugs.
That leads to the other big question Rommel said potential big pharma partners used to ask him: Once a company has identified several highly specific targets, should it try to design a drug that selectively hits them together? Many successful marketed cancer drugs hit more than one kinase, after all.
But Rommel advises proceeding with caution in this area. "When you combine targets, you have to be sophisticated in aligning the mechanism," he explained. The targets might need to be hit simultaneously, or they might need to be hit in a particular sequence. Some might need to be hit intermittently at a high dose while others might need to be hit chronically at a low dose.
Intellikine once had a compound that hit both PI3K and another target, but the biotech eventually dropped the program. As Rommel explained, "The drug will not hit both targets equally hard – so which do you prioritize?"
All of which isn't to say that the oncology field won't eventually see single-pill combos like Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) for HIV, but Rommel noted that the components of Atripla were developed, optimized and FDA approved individually before being combined. "We need to be successful first with the selective drugs, and then we need to combine them," he said.
Again, the PI3K pathway serves to illustrate the point. Rommel said inhibiting PI3K triggers multiple adaptive responses – signaling cross-talk, pathway feedback mechanisms – within tumor cells. The result is that in addition to resistance at the molecular level, drug developers may have to contend with resistance at the cellular level. Combination therapy will be critical in overcoming such resistance, Rommel said, but optimizing highly targeted drugs individually will provide more flexibility to create a wide variety of combinations needed to outsmart a wide variety of tumors rather than getting locked into one particular combination.
But even Rommel won't say there's not a role for broader acting cancer drugs.
"I don't like the one size fits all approach," he said, noting that pan-PI3K inhibitors might be applicable in certain tumor types, such as those that depend on the PI3K pathway, but in which a PI3K alpha mutation is not the key driver.
"In science, people always come up with these dogmas," Rommel said. "The real dogma is: There is an approach that might work for one question, but it is not always advisable for everything."