mTOR | Pharma Strategy Blog

Targeting PI3-kinase and mTOR in cancer

By MaverickNY on February 24, 2011

Today, I’m heading off to San Francisco for the AACR Special Conference on Targeting PI3-Kinase and mTOR in cancer. For those of you needing a brief primer on the pathway, you can find more about it in this 2010 post, which vies with one about ipilimumab in melanoma as the top two posts on Pharma Strategy since the end of October.

You can view the PI3K-mTOR program here.

I’m really excited to be attending this event – a lot of the ‘big guns’ in the PI3-kinase field are speaking at this event, including Lewis Cantley, Jeffrey Engelman, David Sabatini, Carlos Arteaga, Neal Rosen, Gordon Mills and many others.

There are also presentations from scientists at various Pharma and Biotech companies with PI3-kinase inhibitors in development, so it won’t just be about the basic translational research per se, but also about how the R&D is progressing to date with new therapeutics.

If anyone is at the meeting, please do stop and say hello – it’s always nice to meet readers in person – I bumped into a few at last weeks ASCO/ASTRO/SUO GU cancers symposium, for example.

I’ll be tweeting a few snippets from the conference, including tonight’s keynote by Jose Baselga (Mass General Hospital), but excluding unpublished data, under the hashtag #PI3K. The aggregated tweets from that hashtag will be captured between now and Saturday in the widget below for easy following for those remote and interested in this sub-specialty:

<a href="http://www.coveritlive.com/mobile.php/option=com_mobile/task=viewaltcast/altcast_code=26e3075cca" >AACR PI3K-mTOR Special Conference</a>

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Ariad and Merck's ridaforolimus succeeds in phase III sarcoma trial

By MaverickNY on January 18, 2011

This morning my emails greeted me with an announcement that the long awaited phase III SUCCEED trial data in soft tissue sarcomas from Ariad and Merck has been announced:

“… showing that ridaforolimus, an investigational oral mTOR inhibitor, met the primary endpoint of improved progression-free survival (PFS) compared to placebo in the Phase 3 SUCCEED trial conducted in patients with metastatic soft-tissue or bone sarcomas who previously had a favorable response to chemotherapy.

Merck is currently developing ridaforolimus in multiple cancer indications under an exclusive license and collaboration agreement with ARIAD. Complete findings from the SUCCEED trial will be submitted for presentation at an upcoming medical meeting this year.”

In the analyst teleconference I just listened to, the CEO Harvey Berger also stated that aside from presenting the data at a meeting this year, Merck was planning on filing the data with the regulatory authorities.

The good news is that no new safety signals have emerged and the common side effects reported previously, ie stomatitis (mouth sores), fatigue, diarrhea and thrombocytopenia appear unchanged.

Correspondence and interviews with a number of the SUCCEED trialists in the US and EU over the last year has taught me that ridaforolimus is generally well tolerated and quite a few patients have experienced prolonged stable disease (SD) while on ridaforolimus maintenance therapy between chemotherapy.

According to Ariad, the initial aggregated data from SUCCEED was as follows:

“Based on the full analysis of 552 PFS events in 711 patients, determined by an independent review committee, the blinded prospective study achieved its primary endpoint, with a statistically significant (p=0.0001) 28 percent reduction by ridaforolimus in the risk of progression compared to placebo (hazard ratio=0.72). Determination of median PFS for each arm of the trial demonstrated that ridaforolimus treatment resulted in a statistically significant 21 percent (3.1 week) improvement in median PFS (ridaforolimus, 17.7 weeks vs. placebo, 14.6 weeks).

Based on the full analysis of PFS determined by the investigative sites, there also was a statistically significant (p<0.0001) 31 percent reduction by ridaforolimus in the risk of progression compared to placebo (hazard ratio=0.69). Ridaforolimus treatment resulted in a statistically significant 52 percent (7.7 week) improvement in median PFS (ridaforolimus, 22.4 weeks vs. placebo, 14.7 weeks).”

There are several important things to note here:

The PFS is less than a month, but highly significant
The conditions for the SPA (primary endpoint was PFS) appear to have been met
The last patient enrolled early last year, so hopefully the OS data (secondary endpoint) will be ready by the filing and will be positive
The excellent hazard ratios suggest that the curves are well separated, leading me to think/hope that the OS might actually be more encouraging than PFS
PFS is a difficult surrogate end point to measure; many trials end up with a difference between investigator estimate and central review as a result

We also need to look at these results in the context of soft tissue sarcomas (STS) as a disease. By this, I’m thinking about the following issues:

STS is a heterogeneous disease made up of many different subtypes
It is a difficult to treat, aggressive disease and many patients are treated with multiple lines of chemotherapy to progression but sadly still relapse as resistance develops
Some subtypes are highly chemosensitive, some are not
Stable disease and quality of life are valuable to people with sarcoma
The danger of a ‘catch-all’ trial is that the non-responders cancel out the responders, lowering the overall response rate
Did any particular subsets do better on ridaforolimus than others?
Did any biomarkers emerge around mTOR, PI3-kinase, AKT, MEK or some other factor?
What factors were associated with the development of resistance?
If so, would this help us learn what might be a useful combination approach going forward?

Overall, based on what I’ve seen, this data looks promising so far and I’m keen to see more granular data when it is presented at a scientific meeting soon… Perhaps the data made the ASCO late breaking abstract cut-off this month?

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LKB1 is a master kinase in cancer

By MaverickNY on September 1, 2010

"LKB1 is a master kinase"

What a great subheader in a paper last year by Reuben Shaw (journal link below).

Liver kinase B1 (LKB1) first got my attention at the AACR lung cancer meeting in San Diego earlier this year, when a couple of translational researchers mentioned it during informal discussions about how it might play a critical but subtle role in lung cancer and potentially other cancers.

Looking at the literature, LKB1 was first identified as a tumor suppressor gene on human chromosome 19p13, responsible for the inherited cancer disorder Peutz-Jeghers Syndrome (PJS). However, the interest at the AACR meeting centred around it being one of the most commonly mutated genes in sporadic human lung cancer, including some subtypes of non-small cell lung carcinoma (NSCLC).

Of course, being very interested in potential druggable targets, I was trying to get my head around this particular kinase. Several scientists and researchers explained to me patiently that LKB1 is involved in energy levels and metabolism, rather than cell signalling per se, so it kind of went by the wayside as other interesting targets came up lately, associated with small molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies.

Still, the fact that LKB1 and AMPK control cell growth in response to environmental nutrient changes stuck in the back of my mind while I quietly wondered whether it would eventually have it's day.

Fast forward to an AACR press conference this morning about the role of metformin, a biguanide therapy for managing hyperglycemia and diabetes, in the role of chemoprevention. I'm going to write more about that meaty topic in another more detailed post tomorrow, but what fasinated me was the mention by Dr Michael Pollak about metformin altering cell energy levels, ie a control system that senses cell energy supplies and low reserves.

It was also mentioned that the activation of the LKB1-AMPK pathway downregulates gluconeogenesis. This process represents the export of energy from hepatocytes to the organism in the form of glucose. In turn, this reduces blood glucose concentration, which results in a secondary decrease in insulin level.

Essentially, the inhibition of hepatic gluconeogenesis is now felt to be a key process underlying the utility of biguanides in the therapy of type II diabetes.

What is interesting on several levels is:

Studies showing raised levels of free or circulating IGF1 may be associated with an increased risk of developing cancer
Epidemiology studies amongst people with diabetes taking metformin who may have a lower risk of developing cancer

Of course, when we look at the broader picture, we can see the interactions across several pathways, which makes the whole situation highly complex:

Source: University of Dundee

Clearly, there is now enough evidence to warrant researching the effects of metformin in cancer prevention, especially given that it is orally available, has had no long term safety issues and is now generically available. These factors, coupled with a greater understanding of the biology of the involved pathways may make a productive new area of cancer research.

Tomorrow, I will cover the latest research involving metformin for chemoprevention in colorectal and lung cancers in more detail.

Shaw RJ (2009). LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta physiologica (Oxford, England), 196 (1), 65-80 PMID: 19245654

Shackelford DB, & Shaw RJ (2009). The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nature reviews. Cancer, 9 (8), 563-75 PMID: 19629071

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PI3-kinase (PI3K): a hot topic in cancer research

By MaverickNY on July 19, 2010

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 Future:

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

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#AACR10: The Kinase Dilemma

By MaverickNY on April 26, 2010

There are a lot of clinical trials out there right with tyrosine kinase inhibitors; unfortunately many will fail because they were rushed into phase II or III trials without thinking through all the options. There are, however, some smart companies out there who do think.

What was noticeable at AACR this year, was the surfeit of posters and presentations regarding logical combinations designed to eliminate escape routes and hence resistance. For example, cross-talk is a common problem between ligands, eg IGF-1R and EGFR, so combining the two may reduce the problem but that isn't the whole story.

Feedback loops also exist, so targeting PI3-kinase alone is less likely to be effective than targeting both PI3-kinase and mTOR. Neal Rosen from MSKCC showed some interesting data to this effect and argued cogently that oncogenes tend to lead to constitutive negative feedback. He also noted that the BRAF mutation predicts for sensitivity to MEKi, for example. Michael Korn also discussed the feedback activation loop between the RAS-ERK and PI3K pathways and how the inhibition of autophagy (where cells self digest themselves) can enhance apoptosis and the anti-tumour effect with smart combinations.

Targeting both MEK and AKT may therefore also have more effect than either alone, as you can see in the chart below:

Source: Array Biopharma

In a recent trial reported at the the ASCO GI meeting in January, Merck described an elegant design where IGF-1R, EGFR and AKT inhibitors were all combined to target advanced pancreatic cancer, with promising early results. I thought this was a prescient approach at the time, since it clearly sought to eliminate both cross-talk and feedback, so it was interesting to see numerous researchers advocating similar approaches in different tumour types based on the overexpression profiles at AACR last week. The design is based on rational biochemistry, which regular PSB readers will know I'm a big fan of, rather than randomly adding a kinase inhibitor to whatever is the standard chemotherapy of the day in a haphazard blunderbuss approach.

There are a number of MEKi and AKTi inhibitors out there (I counted nearly a dozen last time I checked), as well as a plethora of PI3-kinase and mTOR inhibitors, either alone or in combination. Merck and AstraZeneca announced an interesting deal earlier this year to jointly pursue research with their AKT (MK-2206) and MEK (AZD6244) inhibitors. This collaboration makes a lot of sense biochemically. Novartis (a client) have one of a broadest kinase pipelines in the industry and just added to it prior to AACR in a deal with Array BioPharma to license their MEK inhibitors, of which ARRY-162 is the lead candidate.

The compounds that ultimately win the race may not necessarily be the ones furthest ahead in clinical trials right now, but the ones with the smartest clinical trial designs to eliminate some of the issues associated with kinase inhibition – cross-talk, feedback, feed-forward loops and additional mutations.

MEKi and AKTi are two of my favourite kinase approaches right now because they offer the flexibility to add to existing TKI's such as erlotinib, sorafenib or everolimus, for example, potentially improving the outcomes further in a variety of different cancers, never mind the future combination possibilities. It's going to be a very interesting and hot area to watch in the near future, that's for sure.

If you have any thoughts or questions on this fascinating topic, please do add them in the comments below.

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Merck and Schering Plough's new robust pipeline

By MaverickNY on March 2, 2010

"Merck's newly integrated pipeline follows a comprehensive prioritization process that closely examined all compounds in development at both companies prior to the merger. Candidates were prioritized based on a series of criteria, including potential for impact on human health, molecular characteristics, stage of development, probability of success and commercial potential.

The new combined pipeline is composed of small molecules, vaccines and biologics targeting a broad range of unmet medical needs including: atherosclerosis and thrombosis, cancer, diabetes, hepatitis C infection, insomnia, and schizophrenia.

Merck's pipeline is particularly strong in therapeutic areas in which both companies have long-established research programs, such as cardiovascular disease and infectious diseases; Merck has eight investigational medicines in each of these two categories."

Source: Merck

Yesterday, Merck announced the results of their pipeline evaluation and prioritisation following the recent merger with Schering Plough. There are 19 projects in phase III development across all therapy areas. Although the two key areas for both companies were the same (cardiovascular and infectious diseases), there was little overlap, so the combined company now has 8 compounds in each area to manage.

What was interesting to me though, was what would happen in oncology where there was some overlap?

It now seems that Merck's IGF-1R inhibitor, dalotuzumab, which is in phase II development, has been selected as the lead cancer candidate. This is good news for those interested in the IGF-1R pathway after recent events that saw Roche handing back R1507 to Genmab and Pfizer's figitumumab hitting some roadblocks in newly diagnosed non-small cell lung cancer.

We know that adding an EGFR inhibitor reduces cross-talk between EGFR and IGF1R and including either an AKT or mTOR inhibitor may also reduce opportunities for resistance developing. Merck recently presented data at the ASCO GI meeting in pancreatic cancer with several drugs in combination, including metformin to reduce the hyperglycemia effect. The scientists and clinicians did a nice job thinking some of the issues through and managing the effects considering the side effect issues seen with figitumumab.

Of course, the co-development of the mTOR, ridoforolimus, continues in conjunction with Ariad and new data from the phase III trials in soft tissue sarcoma is eagerly anticipated by many at ASCO in June.

In my view, the most interesting cancer agents that Merck has are probably in phase I, time will tell what happens to those.

Afinitor extends life for renal cancer patients

By MaverickNY on October 9, 2008

A new drug in development, Afinitor (everolimus, RAD001) appears to extends life without tumour growth by almost 5 months compared to 1.9 months with placebo. In addition, a quarter of the patients in the study remained progression free beyond 10 months of treatment. This is the first therapy to show significant benefit after failure with initial tyrosine kinase therapy (Sutent or Nexavar). It is currently being reviewed by the FDA for treatment of advanced kidney cancer after failure of initial therapy.

Initial therapy with kinase inhibitors has demonstrated signifcant progression free survival (PFS). Nexavar, for example, demonstrated a doubling of median PFS in patients with no prior
cytokine therapy of 25 weeks vs. 12 weeks with placebo. Sutent was compared to interferon-alpha and demonstrated a PFS of 47.3 weeks compared to 22 weeks with interferon-alpha.

What makes Afinitor different and why does it appear to work well, even in patients who have failed stand therapy? Well, the answer lies in it's mechanism of action. Both Sutent and Nexavar are multiple kinase inhibitors, principally of Vascular Endothelial Growth Factor (VEGF), that appears to be important in renal cell cancer. Solid cancers survive by extending their network of tumour vasculature, a process known as angiogenesis. Inhibiting VEGF therefore inhibits the tumours ability to grow. They also inhibit Platelet Derived Growth Factor (PDGF), which is important in cell proliferation.

Afinitor, on the other hand, inhibits the mammalian target of rapamycin (mTOR) is an intracellular protein that
acts as a central regulator of multiple signaling pathways (IGF, EGF,
PDGF, VEGF, amino acids) that mediate abnormal growth, proliferation,
and angiogenesis in cancer. mTOR is a critical component of the PI3K/AKT pathway, a key signaling pathway that is frequently dysregulated in many cancers.

Image courtesy of Novartis Oncology

By targeting a different pathway, the activity of the tumour can be further reduced, even after patients have stopped responding to their initial therapy. This is one of the new key approaches to attacking cancer – find multiple inhibitors of different critical pathways and then determine the best sequencing for the regimens, thereby improving survival.

All three drugs mentioned so far are oral therapies, which are convenient and easy for cancer patients to take each day. Another drug approved for renal cancer is Torisel (temsirolimus), a mTor inhibitor that is given by intravenous infusion over 30-60 minutes on a weekly basis. This drug significantly extended survival in renal cancer patients compared to interferon-alpha treatment (10.9 vs. 7.3 months). When standardised in weeks to enable comparison to Sutent, this means the PFS was approx. 49 weeks compared to 47 for Sutent.

It should be noted that rare bowel perforations are possible with these therapies, a class effect of inhibiting the VEGF pathway. Sutent and Nexavar have also been asssociated with raised blood pressure and hypertension, whereas Torisel may result in hyperglycemia and hyperlipemia. This may result in the need
for an increase in the dose of, or initiation of, insulin and/or oral
hypoglycemic agent therapy and/or lipid-lowering agents, respectively.

Additional new results with these agents are expected at the Annual Society of Clinical Oncology meeting in mid 2009. Afinitor is currently being evaluated by the FDA and EMEA for approval and could be available on the market by March-April 2009.

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