Recently at a couple of scientific cancer meetings, American Urology Association (AUA) and American Society of Clinical Oncology (ASCO), Frank McCormick described a fascinating talk about how a wac-a-mole approach to figuring out how the phosphatidylinositol 3′-kinase (PI3-kinase or PI3K) pathway could be targeted effectively with therapeutics. The reason for research in this area is PI3K has been shown to play a major role in proliferation and survival in a wide variety of human cancers, thus making is a potential target for therapeutic intervention.
I’ve been following this target for a couple of years now and data is now starting to emerge that’s worth discussing on a broader scale, given the implications. Here’s a quick snapshot of the PI3K pathway and related pathways:
Source: Workman et al., Nature
As many of us well know, however, simply targeting one element of an aberrant pathway can lead to cross-talk and feedback loops as the cancer tries to maintain the signals important for it’s survival, so a more cunning approach is needed whereby the escape routes are closed off one by one by targeting different kinases as well as PI3K.
McCormick’s talk was a fascinating lecture that basically went through multiple pathways explaining, ‘well we tried X and this happened, so we tried blocking Y as well and this happened…’ kind of approach in a very logical and systematic fashion. Eventually, all options will be explored and a new paradigm might emerge.
It was therefore with great interest that I read a series of new papers in AACR’s journal, Clinical Cancer Research (see references below) over the weekend on both the pathway itself, and also new data with targeted PI3K agents in both breast and renal cancers.
The Data so far:
Miron et al., looked at PI3K mutations in in situ and invasive breast carcinomas and reported:
“This is the first study to show that PIK3CA mutation is a relatively early event in breast tumorigenesis preceding invasion because the frequency of PIK3CA mutations was the same in pure DCIS as in DCIS adjacent to IDC and in IDC.”
Given the frequency of mutations was the same for the 3 groups they studied (pure ductal carcinoma in situ (DCIS), DCIS adjacent to invasive carcinoma, and invasive ductal breast carcinomas), the data suggest that the PI3K mutation may play a greater role in breast tumor initiation than in invasive progression.
If this is the case, targeting PI3K early, for example in neoadjuvant therapy, may have a positive beneficial effect.
In the O’Brien paper, the researchers looked for predictive biomarkers of sensitivity to Roche/Genentech’s PI3Ki, GDC-0941 in preclinical models of breast cancer:
“We found that models harboring mutations in PIK3CA, amplification of human epidermal growth factor receptor 2, or dual alterations in two pathway components were exquisitely sensitive to the antitumor effects of GDC-0941. We found that several models that do not harbor these alterations also showed sensitivity, suggesting a need for additional diagnostic markers.”
Identifying suitable biomarkers in preclinical studies, such as the HER2 amplification and the PIK3CA mutation (but not PTEN deficiency) previously identified in other studies and now validated in O’Brien et al’s GDC-0941 study, will hopefully help in better design of future clinical studies. They also noted that decreased ERBB3 expression in PIK3CA mutant cell lines, and ERBB3 expression was increased in response to treatment with a PI3K inhibitor, suggesting that ERBB3 expression levels might be used as a biomarker for high activation of PI3K signaling and increased sensitivity to PI3K inhibitors. This kind of rigourous approach would potentially enable selecting which people are most likely to respond up front to the agent, rather than exposing those who are unlikely to get a response to additional toxicities and side effects.
In a well written editorial, Turke and Engelman, also emphasised that:
“A novel expression profile was developed to identify other breast cancers sensitive to PI3K inhibitors. These expression studies highlighted feedback networks connecting TORC1, PI3K, and mitogen-activated protein kinase (MAPK) pathways, and underscored the potential for combination therapies.”
They also went on to observe:
“It will be interesting to determine if PI3K inhibitors induce substantial apoptosis in vitro and tumor regressions in vivo in these cancer models (without HER2 amplification or PIK3CA mutation). Of course, it will be crucial to assess biomarkers identified in laboratory studies in clinical samples from patients who respond to PI3K inhibitors. Neo-adjuvant trials in breast cancer patients can be leveraged to address these translational goals, because they correlate clinical efficacy and pathologic signs of response (e.g., changes in Ki67 levels and induction of caspase cleavage) with the presence of potential biomarkers.”
In another study, Cho et al., looked at the effects of a dual PI3-Kinase/mTOR Inhibitor
NVP-BEZ235 compared with rapamycin in renal cancer (RCC) with BEZ235 (Novartis). The proof of concept for mTOR has already been shown clinically with the approval of two drugs in this indication, temsirolimus (Pfizer) and everolimus (Novartis):
“These agents induce only modest tumor regression and extend progression-free survival only a few months in most patients.”
The big question here is whether targeting PI3K as well as mTOR would have any extra beneficial effects? The results demonstrated that dual inhibition of PI3K/mTOR with BEZ235 induced growth arrest in RCC cell lines both in vitro and in vivo more effectively than inhibition of TORC1 alone. If reproduced in the clinic, this may offer a new and more effective approach to treatment of the disease.
The PI3-kinase field is particularly interesting, with several companies snapping up PI3K inhibitors including sanofi-aventis (from Exelixis) and more recently, Infinity (from Intellikine). Other oncology companies already have some in their pipeline, such as Novartis (BEZ235) and Roche/Genentech (from Piramed). Meanwhile, smaller biotechs such as Semafore and Calistoga also have some promising early phase compounds in development. Some of these compounds target PI3-kinase alone, while others target PI3K and mTOR.
This is not going to be a straightforward approach to targeting cancer and identifying biomarkers along the way will be key, as well working out the best combinations that might make a more effective therapeutic approach than single agent activity. Figuring out when best to test these agents (early or late) will also be critical. The I-SPY breast cancer trials have already led the way in creating protocols for testing novel agents in the neoadjuvant setting in breast cancer, and it may well be that PI3K inhibitors would be a good class to test in this setting based on the new evidence from Miron et al’s study.
What is particularly interesting to me is that PI3K signalling may also have a role to play in asthma and COPD (the area I did my doctoral research in) rather than just cancer. Now that would be really fascinating as the biochemical and molecular biology overlap have long been suspected, but very little research has really evolved this way. Part of that is due to drug manufacturer silos and the inability to effectively spearhead cross-therapeutic research.
It will be fascinating to watch how the PI3K data shakes out in practice over the next few years.
What do you think?
O’Brien, C., Wallin, J., Sampath, D., GuhaThakurta, D., Savage, H., Punnoose, E., Guan, J., Berry, L., Prior, W., Amler, L., Belvin, M., Friedman, L., & Lackner, M. (2010). Predictive Biomarkers of Sensitivity to the Phosphatidylinositol 3′ Kinase Inhibitor GDC-0941 in Breast Cancer Preclinical Models Clinical Cancer Research, 16 (14), 3670-3683 DOI: 10.1158/1078-0432.CCR-09-2828
Turke, A., & Engelman, J. (2010). PIKing the Right Patient Clinical Cancer Research, 16 (14), 3523-3525 DOI: 10.1158/1078-0432.CCR-10-1201
Miron, A., Varadi, M., Carrasco, D., Li, H., Luongo, L., Kim, H., Park, S., Cho, E., Lewis, G., Kehoe, S., Iglehart, J., Dillon, D., Allred, D., Macconaill, L., Gelman, R., & Polyak, K. (2010). PIK3CA Mutations in In situ and Invasive Breast Carcinomas Cancer Research, 70 (14), 5674-5678 DOI: 10.1158/0008-5472.CAN-08-2660
Cho, D., Cohen, M., Panka, D., Collins, M., Ghebremichael, M., Atkins, M., Signoretti, S., & Mier, J. (2010). The Efficacy of the Novel Dual PI3-Kinase/mTOR Inhibitor NVP-BEZ235 Compared with Rapamycin in Renal Cell Carcinoma Clinical Cancer Research, 16 (14), 3628-3638 DOI: 10.1158/1078-0432.CCR-09-3022