Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts from the ‘Pathways’ category

“RAF inhibitors (vemurafenib and dabrafenib) have profound clinical activity in patients with BRAF-mutant melanoma, but their therapeutic effects are limited by the emergence of drug resistance.”

Solit and Rosen (2014)

For today’s post on Science Fridays, I wanted to take a look at an overview paper, published in Cancer Discovery, from two researchers in the metastatic melanoma field who have been looking at multiple mechanisms of resistance.  It’s an important topic because while we have seen incremental improvements in outcomes for this disease, the 5-year survival rate is still rather poor with only 10–20% of metastatic patients still alive by then.  This is not to disparage the efforts of scientists, clinicians or companies working in this space, far from it, but there is is clearly a need for new therapies, strategies and combinations, given the high unmet medical need that exists.

We still have a long way to go in moving the survival needle dramatically.

It wasn’t until I searched for related blog posts to link to this one that I realised how much we have already covered on this topic! Regular readers will recall discussions here on PSB on various combinations such as:

  1. RAF + MEK inhibitors (downstream resistance)
  2. RAF + PI3K-AKT-mTOR inhibitors (cross resistance)
  3. RAF + CTLA–4 checkpoint inhibitors (anti-tumour immunity)

to name a few examples.

We have seen that adding a MEK inhibitor to dabrafenib e.g. trametinib can overcome resistance temporarily and add a few extra months before the resistance sets in again. Similarly for PI3K inhibitors tested to date. Adding ipilimumab, an anti-CTLA–4 checkpoint inhibitor held much promise, but the combination was abandoned with the emergence of unexpected liver toxicity.

Results thus far suggest that something else is acting as an escape route, thereby enabling the tumour to continue driving oncogenic addiction to BRAF.

The $64K questions are what is happening and what can we do about it?

We also need to remember that clinical research advances piecemeal based on evidence from preclinical reseach, so we see the logical evolution of BRAF monotherapy -> combos with downstream (MEK) or upstream (NRAS) targets in same pathway -> combos with diagonal (PI3K) pathways etc.

What Solit and Rosen have done is put a nice summary together of the state of play in this disease and the paper (see References below) is well worth reading.

Their main assertion is interesting, namely:

“The common feature of each of these mechanisms of resistance is that they result in activation of ERK signaling that is insensitive to the RAF inhibitor. Thus, RAF inhibitor resistance is often associated with maintenance of activation of the oncogene-driven pathway.”

Two recent papers are cited in support of this theory from Shi et al., (2014) and Allen et al., (2014) – see References below for additional background reading. Both studies used patient samples to look at clonal evolution and the genetic landscape in advanced melanoma. It’s actually quite amazing what unbiased exome sequencing can uncover at the molecular level, not least are the development of new mutations and other functional alterations.

The Shi et al., (2014) study was briefly summarised by Solit and Rosen:

“Multiple biopsies were obtained at different times or from disparate locations from several patients, and more than a single lesion in the ERK pathway was identifi ed in multiple patients typically within
different tumor biopsies.”

They went to note:

“A detailed phylogenetic analysis of multiple progressive lesions from a subset of these patients suggested branching evolution of tumors in which the development of genetic diversity was not linearly associated with time.”

Previously, a case report found distinct mechanisms of BRAF inhibitor resistance were present in two different progressing lesions from a single patient, so the work of Shi et al., (2014) is consistent with this finding. It blows my mind that different lesions in the same patient might behave completely differently though – imagine trying to devise an appropriate and effective clinical strategy in these cases?!

Allen et al’s (2014) work also involved whole exome sequencing (WES) from patient samples:

“WES was performed on paired pretreatment and progression samples collected from 45 patients, of whom 14 developed resistance soon after initiation of therapy (within 12 weeks). They also detected several resistance mechanisms that had been previously identified to confer RAF inhibitor resistance, including mutations in NRAS , MAP2K1, and NF1 and BRAF amplification.”

A third important study in this area from Wagle et al., (2014) adds to the weight of evidence with new mutations developing. Solit and Rosen continued the story:

“Consistent with the preclinical studies highlighted above demonstrating that MEK1 and MEK2
mutations can confer RAF and MEK inhibitor resistance, a MEK2 Q60P mutation was identifi ed in 1 of 5 patients studied. Of greater surprise to the investigators, one patient had a BRAF splice variant lacking exons 2–10 and a second patient had BRAF amplification.”

By now, you can see the sheer variety of changes and adaptations taking place in different studies around the world in some of the top melanoma labs. What do they have in common though?

“One hypothesis to explain this result is that increased abundance of the oncogenic driver (in this case BRAF) in response to prolonged drug treatment results in increased flux through the ERK pathway and restoration of ERK activity above the threshold required for inhibition of cell proliferation.”

The next challenge is to figure how we can approach better therapeutic index and shutting down of the pathways?

“The results suggest that the early adaptive response of BRAF -mutant cells to ERK pathway inhibition may promote the selection of resistant clones that harbor additional genomic events that
confer higher levels of RAF inhibitor resistance. The data also support combinatorial approaches that attenuate the adaptive response, including the addition of a PI3K or AKT inhibitor to the RAF and MEK (or ERK) inhibitor combination.”

The problem with this approach though, is that the neither the BRAF nor PI3K inhibitors have been able to reach or go beyond the single agent dosing schedules:

“As previous attempts to combine MAPK and PI3K pathway inhibitors have been limited by overlapping toxicities, upfront testing of intermittent treatment schedules should be considered.”

This is the also approach that Das Thakur suggested in her work presented at AACR last year, and subsequently published in Nature, to delay the development of resistance to vemurafenib.

I do think this one area where we may well see new trials evolve in advanced melanoma, so we will have to wait for new data before we can see if the strategy is successful at delaying the emergence of resistant clones. It is good to see the evolution of solid preclinical and translational evidence from patient biopsies helping to inform future clinical trial strategies.

In the meantime, the next major milestone I’m waiting for is on Roche/Genentech’s MEK inhibitor, cobimetinib (GDC–0973), which is due to report combination data with vemurafenib (continuous dosing) later this year. It will be interesting to see if this inhibits MEK more completely than trametinib and whether the combination has a better initial outcome than dabrafenib plus trametinib, which added about two to three months of extra survival over dabrafenib alone.

References:

ResearchBlogging.orgSolit DB, & Rosen N (2014). Towards a Unified Model of RAF Inhibitor Resistance. Cancer discovery, 4 (1), 27–30 PMID: 24402945

Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, Chodon T, Guo R, Johnson DB, Dahlman KB, Kelley MC, Kefford RF, Chmielowski B, Glaspy JA, Sosman JA, van Baren N, Long GV, Ribas A, & Lo RS (2014). Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy. Cancer discovery, 4 (1), 80–93 PMID: 24265155

Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, Place CS, Taylor-Weiner A, Whittaker S, Kryukov GV, Hodis E, Rosenberg M, McKenna A, Cibulskis K, Farlow D, Zimmer L, Hillen U, Gutzmer R, Goldinger SM, Ugurel S, Gogas HJ, Egberts F, Berking C, Trefzer U, Loquai C, Weide B, Hassel JC, Gabriel SB, Carter SL, Getz G, Garraway LA, Schadendorf D, & Dermatologic Cooperative Oncology Group of Germany (DeCOG) (2014). The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma. Cancer discovery, 4 (1), 94–109 PMID: 24265153

Wagle N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A, Rosenberg M, Goetz EM, Sullivan RJ, Farlow DN, Friedrich DC, Anderka K, Perrin D, Johannessen CM, McKenna A, Cibulskis K, Kryukov G, Hodis E, Lawrence DP, Fisher S, Getz G, Gabriel SB, Carter SL, Flaherty KT, Wargo JA, & Garraway LA (2014). MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition. Cancer discovery, 4 (1), 61–8 PMID: 24265154

Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, Dummer R, McMahon M, & Stuart DD (2013). Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature, 494 (7436), 251–5 PMID: 23302800

At AACR last year, one of the most revealing presentations was on metastatic melanoma, specifically, some elegant research by Meghna Das Thakur (NIBR) demonstrating that intermittent pulsing of vemurafenib (a BRAF V600E inhibitor) led to less resistance than inhibiting the target 24/7.

Many of us wondered whether such a pulsing approach would be useful for other tyrosine kinase inhibitors (TKIs).

Fast forward to this week.

CD current Jan 2014Neal Rosen’s lab at MSKCC has an interesting new paper out looking at the effects of pulse dosing with PI3K and ERK inhibition, since targeting both has long been suspected to be key in overcoming cross-resistance.

Recall that despite promising preclinical research, most of the early patient trials looking at targeting the PI3K-Akt-mTOR and RAS-RAF-MEK-ERK pathways in combination were, however, disappointing to say the least, both in terms of the side effect profile, and also with respect to clinical efficacy.

These results also applied to combinations with chemotherapy, which were added to either agent to try and induce cell death via apoptosis.

We know that the PI3K pathway is dysregulated in many cancers, so why have the combinations tried to date produced less than optimal results?

Well, Will et al., (2014) showed that:

  1. RAS-ERK pathway is a key downstream effector pathway of oncogenic PI3K
  2. ERK inhibition is required for apoptosis (cell death) to occur with a PI3K inhibitor
  3. It is important to coordinate downregulation of AKT and ERK since both are necessary for induction of apoptosis and antitumor activity
  4. Such an effect can be achieved with intermittent dosing, which will also likely decrease toxicity and allow administration of therapeutic doses

Ah so the same concept that Das explored in metastatic melanoma could also have potential with PI3K and MEK inhibition!

I find this approach fascinating because in the past, when I queried whether we needed to hit two targets maximally and continuously, rather than look at intermittent or minimally effective dosing (MED), industry people were up in arms and sent me more heated emails on this topic than anything else we’ve ever blogged about!

Meanwhile, Rosen himself hinted at this solution in a talk at the AACR Molecular Targets meeting in Boston last year and said a publication was underway to explain their findings. Generally, I don’t report on unpublished findings out of respect to the scientists and thus didn’t mention it in our extensive AACR Targets Coverage, but am delighted this is now a topic for more public discussion.

Part of the conundrum was articulated by Will et al., (2014) in their author manauscript (see below for the link under the Cancer Discovery Online First Section this month):

“Since mTOR and AKT inhibitors reactivate PI3K signaling, we asked whether PI3K inhibitors have more significant antitumor activity, perhaps by inhibiting other PI3K targets in addition to AKT/mTOR.

Selective PI3K and AKT inhibitors were compared in tumors with activation of PI3K pathway signaling in order to assess differences in the biochemical and biologic consequences of their inhibition. Both inhibitors effectively inhibited downstream targets of AKT, relieved feedback inhibition of growth factor receptors, and inhibited cell growth. However, in HER2-dependent breast cancers, PI3K inhibitors, but not AKT inhibitors, caused the rapid induction of a significant degree of apoptosis.

We find that, whereas AKT inhibitors inhibit AKT/mTOR and activate ERK signaling, PI3K inhibitors inhibit both. They cause durable inhibition of AKT signaling but also transient inhibition of RAS activation and ERK signaling, both of which are required for induction of apoptosis. Moreover, induction of apoptosis by an AKT inhibitor is significantly enhanced when combined with a MEK inhibitor.

Our results show that PI3K is upstream of wild type RAS as well as AKT/mTOR, and this causes the therapeutic consequences of PI3K inhibition to be significantly greater than those of AKT inhibition.”

A number of different inhibitors of PI3K, AKT, mTOR and MEK were explored in this research, so the results are not limited to one or two.

One important question that the group sought to address the inhibition issue:

“PI3K inhibitors cause rapid inhibition of ERK in breast cancer cells with HER2 amplification, but P-ERK levels rebound fairly quickly. Even so, this transient inhibition is required for significant induction of apoptosis by these drugs. We asked whether more complete and sustained inhibition of ERK might enhance induction of cell death by the PI3K inhibitor.”

They found that:

“These results suggest that, in some cells, inhibition of other non-AKT targets of PI3K contribute to induction of apoptosis, or that stronger MEK inhibition is required to fully activate apoptosis. Combined inhibition of MEK and PI3K caused more apoptosis than any of the other treatments in all three models.”

This lead to further work and the finding that:

“Pulsatile PI3K inhibition caused initial tumor regression and significantly suppressed tumor growth. The effectiveness of intermittent administration of the PI3K inhibitor and its superior antitumor activity compared to AKT inhibition were confirmed in another HER2 amplified, PI3K mutant breast cancer model, MDA-MB–361.”

The reason for this?

“We hypothesized that the effectiveness of PI3K inhibition was due in part to its combined inhibition of ERK and AKT.”

The Will et al., (2014) article is available online and open access (see here for direct link) – I highly recommend those interested in this field checking it out and reading the nuggets for yourself, it’s well written and easy to follow.

What does all this mean?

It would be hard for me to improve on Will et al., (2014) conclusion that:

“Recently, treatment with more selective PI3K inhibitors has led to greater therapeutic efficacy in lymphomas and in breast cancer with PI3K mutation or HER2 amplification. The ability of any PI3K inhibitor to inhibit signaling adequately is limited by physiologic toxicity. Moreover, attempts to combine MEK inhibitors with `dual specificity’ PI3K or AKT inhibitors have been complicated by severe toxicity at modest doses of these drugs.

The idea that the pathway must be inhibited continuously dominates the clinical development of these drugs.

Our finding that transient inhibition of PI3K is effective in in vivo models suggests that periodic rather than continuous target inhibition is an alternative strategy that would allow adequate pathway inhibition without causing inordinate toxicity or chronic feedback reactivation of receptors.

Thus, combining PI3K inhibitors, MEK inhibitors and, perhaps, inhibitors of key reactivated RTKs, and administering them at high dose on intermittent schedules may be a more effective therapeutic strategy for these tumors.”

Overall, don’t be surprised to suddenly see new clinical trials emerge evaluating intermittent dosing with PI3K and MEK inhibitors. The only questions in my mind is who will be the first to go this route and who will be able demonstrate superior efficacy and tolerability in patients?

The scientific rationale is very solid for intermittent dosing with BRAF V600E inhibitors and now with the combination with a PI3K plus a MEK inhibitor; it will be really interesting to see if such an approach will translate successfully in the clinic.  I hope it does because improving outcomes is ultimately what we are all here for.

Reference:

ResearchBlogging.orgMarie Will, Alice Can Ran Qin, Weiyi Toy, Zhan Yao, Vanessa Rodrik-Outmezguine, Claudia Schneider, Xiaodong Huang, Prashant Monian, Xuejun Jiang, Elisa de Stanchina, Jose Baselga, Ningshu Liu, Sarat Chandarlapaty, & Neal Rosen (2014). Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of
RAS-ERK signaling Cancer Discovery : 10.1158/2159–8290.CD–13–0611

Yesterday evening, Gilead announced that the Data Monitoring Committee (DMC) had recommended early stoppage of the 116 trial, which looks at idelalisib in relapsed/refractory disease in patients who are not eligible for chemotherapy.  These patients usually have comorbidities or are elderly and frail, and often receive chlorambucil or rituximab alone.  The study compared the combination of idelalisib plus rituximab versus rituximab alone.

Fortunately, the early stoppage was for a good reason – the interim analysis demonstrated a statistically significant improvement in PFS in favour of the combination over rituximab alone.  Adverse events were consistent with previous experience of the drug.

I would imagine that Gilead will seek a filing this year in the near future (presumably once the Government shutdown is over) and we can possibly expect a late breaker at ASH.  This is good news for CLL patients and at least six months earlier than expected.

Based on this information, I would also expect approval for idelalisib in relapsed/refractory CLL by ASCO next year, a year ahead of schedule.  The company have already filed in relapsed/refractory NHL, so the FDA will have a solid safety database from which to make an informed decision.

The frontline CLL trial, presented by Dr Susan O’Brien at ASCO, compared the combination of rituximab plus idelalisib to rituximab alone and is still ongoing.  I’m hoping we will have an update on this at ASH in December.

Gilead have undertaken a smart strategy to date with most of their trials in combinations with approved therapies such as rituximab and bendamustine, which will make it easier for community oncologists, who treat the majority of CLL patients, to integrate a new therapy in their existing treatment options. Sometimes, getting these physicians to switch to a new single agent drug from long established practices is harder and slower than people realise.

Adding something to the existing standard of care is a much easier sell to community doctors, who usually have have older, less fit patients than the Academic physicians, who put their younger, good performance patients into clinical trials where possible.

In the runup to ASH, the CLL market is now getting very interesting – and crowded.

Recall that Roche announced their phase III results for GA-101 (obinutuzumab) in the frontline setting for the same patient segment at ASCO. They are expected to gain approval soon, probably before ASH and have breakthrough status in this indication.

Pharmacyclics and J&J previously filed ibrutinib in 3 indications and have breakthrough therapy designation in CLL, NHL and mantle cell lymphoma (MCL) as single agent therapy. Approval is also expected this year.  There is no doubt that they have a potent and effective single agent in these diseases.

Obviously, a lot of people have wondered whether a combination of ibrutinib plus idelalisib will lead to better overall response rates than either alone. I actually asked this question of the companies presenting at a NYAS meeting a year or two ago, and predictably, they weren’t too enthusiastic.

Why?

Well, it’s much harder for two companies to collaborate on joint trials than it is for a company to manage two agents of their own. To this end, I’m always arguing that companies with a broad and deep pipeline are more likely to win out in the long run if they have the components for logical combinations in the disease being evaluated in house.

What does all this mean?

Source: Gilead

Source: Gilead

What this means is that Gilead and Roche are well placed in CLL and indolent NHL, since Gilead can combine idelalisib (PI3K) with their SYK inhibitor (upstream in the pathway like BTK), GS-993, and Roche can potentially combine GA-101 (anti-CD20) with their Bcl2 inhibitor, ABT-199/GDC-0199.

Many of you will recall the preclinical data at AACR earlier this year looking at Gilead’s two agents and demonstrating some synergies worthy of testing in the clinic. This combination is already in the clinic with two phase II studies currently enrolling in refractory CLL, iNHL and other lymphoid malignancies.

What we should look for is not just the initial response rates and PFS from individual trials, but what the impact of inhibiting two or more pathways will have on survival with subsequent therapies over time. Resistance in leukemias and lymphomas can sometimes take a while to take effect and there are multiple targets to aim at, so cycling different novel combinations by line over time will be interesting to watch.

Strategically, it’s not just about the isolated data with one drug in one line of therapy – we may well see a large improvement in 5 and 10 year survival rates for CLL and iNHL in the long term, with a better quality of life for patients – that’s what oncologists really want to see in the future.

These new developments will undoubtedly put pressure on Infinity, since their PI3K delta/gamma inhibitor is much further behind and will need to define a clear and compelling proposition to differentiate IPI-145 from not only idelalisib (PI3K delta), but also obinutuzumab and ibrutinib.

One thing is clear – such a fertile seam of new therapies – ibrutinib, obinutuzumab and idelalisib in the near term, followed by ABT-199 and IPI-145 in the medium term, is going to change the CLL and iNHL landscapes forever.  That’s a good thing for patients, caregivers and oncologists.

ASH is going to be the meeting of the year at this rate… for those of you needing an overview of the leading agents in the CLL/iNHL landscape, check out this pre-ASCO overview here.

1 Comment

Next I’ll be off to the European Cancer Congress (ECC) in Amsterdam. This meeting alternates each year between ECCO and ESMO hosting the event at a different European city.

The last couple of years have seen some nice data that missed the ASCO deadline, other years can bring an update of the already familiar ASCO data. I suspect that this year will be one of those events, with updated PD-1 and PD-L1 data.

If you missed my colleague Pieter Droppert’s ECCO highlights yesterday, you can catch them here, including details of the iPad app and abstracts.

In addition, there were other abstracts of interest that caught my eye, including some solid late breakers:

1. T-DM1 for HER2-positive metastatic breast cancer (MBC): Primary results from TH3RESA, a phase 3 study of T-DM1 vs treatment of physician’s choice. H. Wildiers (Belgium) et al.

The study looks at advanced disease in patients who had received at least two prior regimens. This analysis looks like an interim one, given the full study timeframe is over 3.5 years. I’m particularly curious what the physician choices were to compete with Kadcyla and what the 1 year survival curves look like. It’s a wee bit early to hope that they might separate already, certainly I hope they do!

2. Evaluation of everolimus (EVE) in HER2+ advanced breast cancer (BC) with activated PI3K/mTOR pathway: Exploratory biomarker observations from the BOLERO-3 trial. G. Jerusalem (Belgium) et al.

Originally, I thought this had been presented at ASCO, but the biomarker abstract I found actually referred to BOLERO-2, where they noted that “efficacy was greater in patients with low PI3K expression”, which is an odd finding. The BOLERO-3 data from ASCO presented the initial phase III data for the combination of trastuzumab, vinorelbine and everolimus vs trastuzumab and vinorelbine alone in trastuzumab resistant HER2+ advanced breast cancer. This should be an interesting presentation worth attending.

3. FLT1 gene variation as a major determinant of recurrence in stage I-III non-small cell lung cancer. F. Innocenti (USA) et al.

Many of us familiar with FLT3 in leukemia, but FLT1 is an interesting concept with very little data (or drugs) out there. I will be curious to see if this is a druggable target and where this approach might lead.

4. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. F. Hodi (USA) et al.

If you look at five year survival curves for advanced melanoma in the literature, it’s historically around 20% or so when patients have received IL-2, which is where I would expect ipilimumab to be. Trials with DTIC have shown a much lower rate, at around 8-9%. Not every patient is suitable for IL-2 though, so we may be seeing similar survival rates irrespective of the immunotherapy given, but with very different safety profiles.

One of my favourite cancer pathways is PI3K-AKT-mTOR. It’s dysregulated in some 80% of cancers yet we haven’t really seen a major breakthrough with these agents in solid tumours outside of the stunning Afinitor data in relapsed ER+ metastatic breast cancer from the BOLERO-2 study presented at ECCO in Stockholm two years ago.

There are many different permutations out there from single to dual inhibitors and also specific isoforms of alpha, beta, delta and gamma.

One of the challenges with targeting PI3K is that it activates feedback loops. Thus inhibiting PI3K in advanced prostate cancer activates the androgen receptor, while single agent use in advanced breast cancer can lead to activation of HER3. In addition, there have been mixed results with biomarkers and specific mutations/tumour suppressors to date such as PIK3CA and PTEN. This increases the complexity tremendously and therefore speaks to more careful trial selection based on inclusion criteria and also logical combinations to try and shut down the compensatory pathway.

I was therefore pleased to see a few trials reporting early phase I/II data in this vein:

P017: Evaluation of tolerability and anti-tumor activity of GDC-0032, a PI3K inhibitor with enhanced activity against PIK3CA mutant tumors, administered to patients with advanced solid tumors.

D. Juric, J.R. Infante, I.E. Krop, C. Kurkjian, M.R. Patel, R.A. Graham, T.R. Wilson, J.Y. Hsu, J. Baselga, D.D. Von Hoff

According to the abstract:

“GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform.”

Several confirmed partial responses have been reported and further trials will continue:

“GDC-0032 is a next-generation PI3K inhibitor with promising anti-tumor activity observed in patients with PIK3CA mutant tumors. GDC-0032 is being investigated in combination with endocrine therapies such as letrozole and fulvestrant for patients with hormone receptor-positive breast cancer.”

P079: Hyperglycemia in patients treated with the pan-PI3K inhibitor buparlisib (BKM120): characterization, management, and assessment for pharmacodynamics

A. Azaro, J. Rodon, J.F. Vansteenkiste, Y. Ando, T. Doi, D. Mills, C. Sarr, E. Di Tomaso, C. Massacesi, R.W. Naumann

Source: Novartis

Source: Novartis

BKM120 is also an oral pan PI3K inhibitor that does not target mTOR. Aside from the activation feedback loop effects mentioned earlier, PI3K plays a key role in glucose homeostasis. A number of earlier trials with different PI3K and mTOR inhibitors have reported hyperglycemia as a class effect although they have varied in the degree to which the event occurred.

This study highlights the importance of a potential pharmacodynamic marker (C-peptide) in assessing the insulin response and I’m looking forward to seeing more detail in the poster.

P061: Factors predisposing to development of hyperglycaemia in phase 1 studies involving PI3K, mTOR, AKT and mTORC1 and mTORC2 inhibitors

M. Wong, K.H. Khan, K. Rihawi, S. Bodla, B. Amin, K. Shah, D. Morganstein, S.B. Kaye, U. Banerji, L.R. Molife

Related to the topic of hyperglycemia, the Royal Marsden mined their database for PI3K-mTOR trials and looked at factors that might influence the presence of the glucose spike in order to essentially try and predict which patients were more at risk and improve management. While most patients did not require intervention, but in those that did, metformin and insulin were usually preferred. Interestingly, the main factor emerging in this retrospective study was a prior history of diabetes, which is not totally unsurprising. It will be useful to see if these results can be validated in prospective future trials.

P227: Anti-tumour efficacy of the PI3K inhibitor GDC0941, the dual PI3K/mTOR inhibitor GDC0980 and the MEK inhibitor GDC0973 as single agents and in combination in endometrial carcinomas

O. Aslan, A.M. Farrelly, B. Stordal, B.T. Hennessy

Much has be written about the potential for a PI3K and MEK combination in different tumour types, but so far they haven’t proven to be the home run many of us hoped for.

This preclinical paper looks at cell lines to explore potential targets and synergies in endometrial cancer (EC). They concluded,

“Our data suggest that the mutational status of PIK3CA, PTEN and KRAS can be used as biomarkers to select patients for PI3K and RAS/RAF-targeted therapies. Further, the combinations of the PI3K inhibitors GDC0941 and GDC0980 with the MEK inhibitor GDC0973 are promising approaches for the treatment of patients with PIK3CA, PTEN and KRAS-mutated EC.”

Translating data from simple cell lines to complex human bodies does not always predict response given the variable responses seen from patients with mutations and tumour suppressors in clinical trials. I think it will take a while to tease out what defines and predicts a response in each tumour type much in the same way we saw different effects in advanced melanoma when targeting BRAF with sorafenib versus BRAF V600E with vemurafenib or dabrafenib. The devil is in the details.

And finally, an oral presentation with a very different focus in the PI3K related field that I’m really looking forward to hearing:

#1859 PI3KCA mutations and correlation with pCR in the NeoALTTO trial (BIG 01-06)

J. Baselga, I. Majewski, P.G. Nuciforo, H. Eidtmann, E. Holmes, C. Sotiriou, D. Fumagalli, M.C. Diaz Delgado, M. Piccart-Gebhart, R. Bernards

The authors evaluated:

“The influence of PI3K pathway mutations (PIK3CA, KRAS, BRAF, AKT1) on sensitivity to trastuzumab (T), lapatinib (L), or both agents (L+T) in combination in early-stage HER2-positive breast cancer patients enrolled the neoALTTO trial.”

The goal here is to see the presence of any of the mutations were more likely to lead to resistance and enable better selection of therapy for patients. I will update on this study after the presentation.

More detailed posts and synopses will continue from the meeting itself on Biotech Strategy Blog, where we’ll be sharing our insights and analysis daily.

It’s that time of the year when the annual meeting of the American Society of Clinical Oncology (ASCO) hurtles around with alarming speed out of nowhere and everyone in Pharmaland goes, “ASCO, what already? Is it really June?!” Suddenly the month becomes the focus for many frantic hives of activity.

Immunotherapy

The last two years have seen some unprecedented changes in new therapies emerging to treat several different tumour types, both liquid and solid.  One of the new trends that has begun to emerge is the new class of immunotherapy agents called checkpoint regulator inhibitors.  These include:

  • CTLA-4 (ipilimumab)
  • PD-1 (nivolumab and lambrolizumab)
  • PD-L1 (RG7446)
  • OXO-40 inhibitors (more about those in another post).

This year at ASCO brings forth a lot of new data from the four compounds mentioned. In the video preview we have also attempted to explain how these antibodies work and why they are an important development beyond melanoma. There are data in several tumour types including melanoma, RCC and head & neck cancer at Chicago. In the recent thought leader interview with Dr Robert Motzer (MSKCC), he mentioned PD-1 as a hot topic to watch out for in renal cancer. However, I’m particularly looking forward to seeing the lung cancer data, which has the potential to be really stunning.

In this year’s ASCO video preview, we have included some graphics and an MOA video explaining how these immunotherapies are thought to work. Check it out below!

CLL

Another area that I’ve been watching for a while is chronic lymphocytic leukemia (CLL), which has languished a little in the shadow of it’s CML cousin. Not for long though!

There are a lot of exciting developments here beyond Pharmacyclics BTK inhibitor, ibrutinib. These include new CD-20 antibodies such as Roche’s GA-101 (obinutuzumab) and SYK inhibitors (whatever happened to fostamatinib, one of the hematology highlights of the 2010 ASCO?) where Gilead are now developing an early compound, potentially for combining with their PI3K-delta inhibitor, CAL-101, now known as idelalisib.

In addition, Infinity also have a PI3K-delta inhibitor, although they are further behind in development. We don’t know yet whether greater in vivo potency will translate to the clinic or whether also targeting gamma will add to the efficacy or introduce off-target kinase toxicities.  Either way, it’s good to see so many targets and exciting new agents being explored for this disease.

Breast and Lung Cancers

On the solid tumour front, I was delighted to see new data in HER2+ breast cancer and ALK+ lung cancer.  Interestingly, in both of these cancers, Pfizer and Novartis in particular are making inroads with a number of compounds including everolimus (Afinitor), palbociclib (PD-0332991) a selective inhibitor of cyclin dependent kinases (CDK) 4 and 6, LDK378 and PF-05280014, a trastuzumab biosimilar.

Pancreatic Cancer

My final topic that has some interesting developments is pancreatic cancer.  Since the phase III Abraxane data from the MPACT study was presented at ASCO GI, Celgene have filed with the FDA and received Priority review, with a PDUFA date of September 21st.  An update is expected at ASCO, along with tumour marker data and prognostic biomarker data.  Threshold are presenting their phase III study design for TH-302 in the Trials in Progress section, but given the standard of care may well have changed by the time the data is mature, this may well be a day late and dollar short.

All in all, a good year can be expected for new data emerging at this year’s ASCO.

You can learn more about these topics, including insights on how PD-1 and PD-L1 immunotherapies work from the video highlights by clicking on the image below:

ASCO 2013 Preview Video

My ASCO preview video was freely available for several months but is now part of Biotech Strategy Blog Premium Content.

 

2 Comments

One of the hot topics at this year’s annual ASCO meeting is clearly going to be PD-1 and PD-L1 immunotherapies, following on from the success of BMS’ PD-1 agent highlighted in my ASCO video last year.  By now, we know that it has a generic name, nivolumab, and is being studied in combination with ipilimumab (Yervoy) in metastatic melanoma. You can find the many nivolumab abstracts here.

Understanding how PD-1 and PD-L1 immunotherapy works.

Source: Roche

Interestingly, BMS also now has competition from other big pharma companies, including Roche’s PD-L1 antibody, MPDL3280A, and Merck’s lambrolizumab.  Roche appear to be developing a companion diagnostic, which could mean the responses are different for PD-L1 positive and negative patients.  At least, that would be an intuitive conclusion and a potentially good way to preselect patients who are most likely to respond to the therapy.

In addition, the FDA have already picked up on this class of agents, conferring the almost ubiquitous Breakthrough Therapy status on some of them already, so solid data in the next year or so could mean a fast track to market strategy is possible in this category.

In the battle of the abstracts and sheer depth of data in the PD-1/PD-L1 segment, you can see that Merck are already the poor cousins to BMS and Roche in execution. Just one?  That’s pitiful!  Never a good sign.

What factors need to be considered in looking at the immunotherapy data?

Last night I was searching the abstracts on my iPhone after the local broadband inconveniently went down and also watched the conversations on Twitter, usually a fun experience fishing for and discussing the diamonds in the rough. A couple of things struck me, however, around the immunotherapy data mining and chatter:

Firstly, there’s way too much focus on ORR (overall response rate) and the minutiae of the differences between the different PD-1/PD-L1 agents. It’s far too early to tell much, as we all know that what matters are the randomized phase III trials, trial design and patient selection (specific, catch-all etc). These can all have a huge impact on the final outcomes in large scale randomised studies.

Secondly, ORR is a measure of disease control – it tells us how much shrinkage there is going on at the time of measurement and is based on RECIST. This is partly a hangover form old chemo days, and partly a lack of available biomarkers of response. Let’s not also forget that immunotherapies usually have a delayed effect and while waterfall plots at six months or so are useful, they don’t tell us what the long term effects will be.  How durable will the responses be beyond 6-8 months?  Is there adaptive resistance developing?  What sort of logical combinations and sequencing options can be considered? So many questions to which we have no answers yet.

Thirdly, be very careful when interpreting the abstract data for ORR – sometimes the data is given for all the patients, irrespective of whether they responded or not, and sometimes it is given as a percentage of the patients who actually had some sort of response. You need to compare apples with apples when looking across studies or the conclusions drawn can end up being a little off.

Fourthly, I don’t think ORR is the ideal endpoint.  So what?  What really matters is how long do patients live, do they feel better (or worse) and will they have a better quality of life as a result of taking the medication?  Other obvious but important questions we need to evaluate going forward include:

  • How much of a prolonged effect with PD-1/PD-L1 immunotherapies have over 5 years?
  • What will be their effect on subsequent therapies?
  • Will they boost or hinder sequencing and in which tumour types?
  • Is there a biomarker of response?
  • Is a diagnostic necessary?

Fifthly, combination studies are nice if they lead to improved outcomes, but at what cost will this be achieved? By this, I mean both in terms of safety (remember ipi and vemurafenib were thought to be a logical combo in melanoma until the unexpected AEs scuppered that concept) and also cumulative cost of treatment. None of the new oncology therapies can or will be considered inexpensive these days, especially when the benefit might be measured in only a few months or less.

Overall:

I’m really looking forward to these presentations on PD-1/PD-L1 and will write about them in more detail at the meeting.  It continues to be an exciting area in oncology, as long as the results live up to the expectations.  It’s still unclear which tumour types will benefit most and what the durability will be.  Right now, I have more questions than answers, but as a concept it’s definitely one well worth watching over the next couple of years.

2 Comments

On the final day of the annual 2013 meeting of the American Association for Cancer Research (AACR) in Washington DC, Jeffrey Engelman (MGH) hosted an excellent plenary session on “Cancer Evolution and Resistance” with a series of superb talks not only from himself, but also Neal Rosen (MSKCC), Todd Golub (Broad Institute) and René Bernards (Netherlands CI).

If this session is included in the webcast, I would highly recommend watching the whole thing several times, as it was one of the meeting highlights for me. Despite being on the very last day, the large hall was pretty packed and well worth waiting for. You can check availability of the AACR 2013 webcast talks here.

I’m going to focus on some of the specifics in NSCLC from Engelman’s talk for this update.

Where are we in the quest to improve outcomes in lung cancer?

Jeff Engelman, courtesy of MGH

Jeff Engelman, courtesy of MGH

Engelman discussed the basics of what we know about adaptive resistance to TKI therapy in solid tumours – most of them (EGFR and ELM4-ALK in lung, BRAF in melanomas, HER2 in breast, and cKIT in GIST) typically being in the range of 8-11 months, with only GIST seeing an impact for nearly 2 years (20 months).

Thus we can see that the resistance develops over time as mutations and amplifications in the tumour evolve in adaptation to the initial efforts to inhibit the target. Indeed, approx. 50% of EGFR lung cancers develop the T790M mutation, while ~33% of resistant ELM4-ALK cancers show new mutations (e.g. L1196M, G1269A and others).

The development of these changes essentially serves as a way to bypass tracks and and continue to allow downstream signalling of PI3K and MEK to occur, thereby driving growth and cell survival. What then happens is a myriad of other pathways become activated to help drive signalling, for example MET, HER2/HER3, IGF1R etc in EGFR driven cancers and EGFR and cKIT amplification in ALK lung cancers.

As an analogy, think of this process like a road traffic system – if the route into New York from New Jersey was cut off at the Holland Tunnel, so traffic would increase to the Lincoln Tunnel or Verrazano Bridge and if those were cut off, traffic would then flow onto the George Washington Bridge, as it adapts and seeks new escape routes from the original destination.

Eventually, the cancer evolves further with defects in growth arrest and apoptosis, as seen with transformation from NSCLC to SCLC in some patients with EGFR cancers, and even changes in the microenvironment through epithelial mesenchymal transition (EMT) and loss of BIM.

The key question is what can we do about overcoming or delaying resistance?

One strategy would be to evaluate more potent inhibitors e.g. LDK378 instead of crizotinib in ELM4-ALK cancers. Another might be to explore logical combinations to address shutting down the bypass tracks. A third might be to add in a new inhibitor to target the specific mutations that evolve e.g. T790M inhibitor in the case of EGFR driven cancers when it appears.

Some of these trials are already underway and we should have more data soon.

Another way, as we saw with the last post on metastatic melanoma, is to identify mechanisms of resistance using laboratory models and lab specimens. This approach can potentially lead to more rational drug development in the clinic. Traditionally, scientists have induced resistance in mice, looked for the mechanisms (a process that can take 1-2 years), validated them in lab samples of patients, and then treated with a new treatment strategy.

This process is obviously time consuming though and not every patient can wait that long for the answer. Engelman then explained how they are looking at ways to streamline the process in Boston. After the mouse resistance experiments are completed, they have added in a drug combination screen to look for logical treatment strategies i.e. what can be added to the original drug to overcome resistance?

A very elegant example was given for EGFR lung cancer where they evaluated 78 test drugs in a screen with and without gefitinib to determine those which led to cell death. Other examples were given for ELM4-ALK cancers.

The screen results suggested that most of the resistant models produced 3-6 hits. These might include adding a MET inhibitor to an EGFR inhibitor in EGFR mutant cancer, an EGFR inhibitor in MET amplified cancers and a SFK inhibitor in the case of ELM4-ALK cancers, for example.

These results are still early, but they do look very promising. Validation studies are still needed, but early studies they performed suggested that the hits are indeed showing efficacy in vivo.  A preclinical example for this concept was shown in vivo by adding ABT-263 (Bcl2 inhibitor) to gefitinib and seeing first a rise in tumour growth with the EGFRi and then a large drop in volume when either ABT-263 or AZD6244 (MEK) was added.

Based on the exciting initial concepts in animals, they are now moving to patient derived models since next generation sequencing (NGS) can help identify the mechanisms of resistance and combined with the drug combination screens, we may see more individual level treatments for patients on a case by case basis.  These might be based on large scale (over 100 cell lines) testing derived from resistant biopsies to identify effective combinations and match them to the relevant biomarkers.  It sounds easy and obvious, but few centres are doing this in practice.

This is true personalised medicine in action.

It is also pretty exciting to me as we know that cancer, even in different patient tumours, is very heterogeneous and requires a more personalised rather than a one size fits all approach. As Engelman observed,

“Heterogeneity of resistant clones within individual patients may pose additional challenges to overcome resistance.”

The second half of his really excellent talk focused on the use of sequential biopsies in patients to explain the heterogeneity and how it can lead to transformation from NSCLC to SCLC and back again in response to treatment with an EGFR inhibitor. That’s an in-depth discussion for another day though, but suffice to say it was a fascinating topic.

And finally…

I can see these novel and applied techniques eventually moving very fast and adopted in top level Academic centres where they have the resources and knowledge to marry basic and translational research with clinical practice in early stage trials, but for many Community or even regional Academic physicians, this will be virtually impossible without referral of patients to clinical trials in the Academic centres, at least for now.

Ultimately, we will see more improvements in treatment for lung cancer when we figure out not only the targets, but also how to overcome adaptive resistance, add logical new combinations, and select future treatment based on biopsies as the tumour evolves its response to each line of therapy. Treatment will essentially need to be chosen on an individual patient basis in the long run by evaluating adaptive resistance to each new combination over time.

The idea that we can use mouse models and drug combination screens with sequential patient biopsies to better understand the adaptive response to therapy over time is not new but few have managed to put processes and strategies in place to make this happen in real time. Patients often can’t wait 2 years or more for a new combination trial to open, but the Boston approach is very promising and I’d like to applaud all those at the Boston group (MGH, Dana-Farber, MIT/Broad etc) for their groundbreaking work in this field. Keep your eyes peeled for more updates in this exciting area of research!

Today is the 1000th blog post here on PSB, a milestone I never imagined actually reaching while writing the inaugural and rather boring post way back in 2006. At that time, 10 posts seemed a lot, never mind 100 or 1000! Anyway here we are, thus the facing the new dilemma of what to write about to celebrate the event.

The nice thing about having a following on Twitter is a ready supply of suggestions and papers from readers. Today’s suggestion comes from Angela Alexander (@thecancergeek), a Post Doc in breast cancer research at MD Anderson who asked if I had seen the exciting new phase II data on MEK inhibition in lung cancer from Pasi Janne’s lab. I’ve long been an admirer of his work, so it is fitting the data has just been published in Lancet Oncology this week (reference below).

Background on KRAS in lung cancer:

KRAS is a particularly tricky gene target because some tumours are seriously addicted to this oncogene, making it tough to completely shutdown from a pathway perspective. Part of the reason is that few drugs possess sufficient therapeutic index and thus resistance can occur fairly early. Recently, though, a number of companies have been exploring targeting downstream of KRAS to see if that approach could attentuate the driver activity in some way. One of these targets is MEK, which many of you will be familiar with in metastatic melanoma, where MEK inhibitors have been shown to be an effective strategy in combination with BRAF inhibitors to produce improved outcomes.

KRAS has been found to be abnormal, or mutated, in approx. 20-25 percent of patients with non-small cell lung cancer (NSCLC), making it the most frequent of the mutations seen in this disease.  We also know that KRAS mutations predict a poor response to EGFR inhibitors and are a negative prognostic indicator.  Finding therapeuetic strategies to overcome KRAS are therefore a high priority in clinical research.

What is the latest study about?

Janne et al., (2012) performed a simple but elegant phase II study looking at the impact of adding a MEK inhibitor, selumetinib (AZD6244/ARRY-142886) from AstraZeneca and Array to standard chemotherapy, docetaxel (Taxotere) to determine whether targeting KRAS indirectly would impact overall survival (OS) and allow patients to live longer. Selumetinib targets both MEK1 and MEK2 and previous phase I trials suggested a promising safety and efficacy profile to warrant further investigation.

To get an idea of the complex logistics involved in the study, 422 patients were screened from 67 sites in 12 countries, of whom 87 whom previously received initial chemotherapy and had both NSCLC AND the KRAS mutation were selected to participate in the trial, indicating an incidence of 20.1% for KRAS-positivity in this sample:

Source: Jänne et al., (2012)

Half the sample (n=44) were randomised to receive standard docetaxel chemotherapy (75 mg/m2 q3w) plus selumetinib capsules (75 mg BD) and the other half (n=43) received docetaxel plus placebo. Both groups were treated until progression or toxicities were unacceptable. Subsequent therapies were allowed, but not crossover.

The primary endpoint for this study was OS and secondary endpoints included PFS, objective response and others such as safety.

What did they find?

Now, first up I would expect the docetaxel alone group to have an overall survival in the second-line setting of around 5-6 months. In this trial the MOS for the placebo group was 5.2 months, which is in line with expectations. However, the selumetinib arm had a near doubling in MOS to 9.4 months, which I think is quite impressive in a very difficult to treat subgroup. PFS also saw a doubling from 2.1 months in the docetaxel alone group to 5.3 months in the docetaxel plus selumetinib group.

Toxicities appeared to be in line with previous trials – selumetinib tends to increase grade 3/4 events when combined with docetaxel i.e. neutropenia (67%) compared to the docetaxel alone group (55%), febrile neutropenia (18% vs. 0%) and asthenia (9% vs. 0%).

What can we conclude from this study?

I thought these results were very promising, although of course, the caveat is that it’s early days yet and a larger phase III multi-center trial is needed as a confirmatory study – not all phase II trials will yield positive data once they complete phase III so we cannot project that far yet. The main added toxicity, myelosuppresion, is to be expected given that it is likely additive to the existing effect seen with docetaxel alone.

This is, however, the first time I can recall seeing very solid evidence that adding a MEK inhibitor to standard chemotherapy in second-line NSCLC significantly improved overall survival in patients with KRAS mutations.

Overall, these results are encouraging and definitely warrant a phase III confirmatory trial with docetaxel and selumetinib in the second-line setting for NSCLC patients with the KRAS mutation.

References:

ResearchBlogging.orgJänne, P., Shaw, A., Pereira, J., Jeannin, G., Vansteenkiste, J., Barrios, C., Franke, F., Grinsted, L., Zazulina, V., Smith, P., Smith, I., & Crinò, L. (2012). Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study The Lancet Oncology DOI: 10.1016/S1470-2045(12)70489-8

New York City NYC view Photo Credit: Sally ChurchThis week I’m attending an interesting 2-day conference on PI3K at the New York Academy of Sciences (NYAS).

It brings together a broad faculty of researchers in the field looking at novel aspects of the PI3K-Akt-mTOR pathway in depth.

One aspect that has become clear with these compounds is that there’s probably more that we don’t know than we do – it’s a highly complex network of nodes and cause-effect that needs to be unravelled.

We do know a few things though, for example, PI3K and mTOR are often activated in advanced disease and can cause resistance to therapy as we have seen with aromatase inhibitors in ER+ disease and trastuzumab in HER2+ breast cancer.  We also know that inhibiting PI3K or mTOR can lead to activation of compensatory pathways that serve to drive oncogenic signalling and tumour survival.  It’s complicated!

The most advanced agent in the PI3K class is probably Gilead/Calistoga’s GS-1101 (formerly CAL-101), which is a delta isomer inhibitor being evaluated in B-cell hematologic malignancies such as mantle cell lymphomas (MCL), indolent NHL and CLL.  After promising phase I and II trials, it has now moved into randomised controlled phase III trials.

Yesterday, Langdon Miller (Gilead) gave a nice overview of the GS-1101 program. One couldn’t help but marvel at the waterfall plots obtained to date, along with the before and after pictures of a women in her 40’s with refractory CLL – a dramatic difference – she looked like a completely different person!  Of course, there are a number of questions that need to be addressed next:

  • Is survival prolonged in heavily refractory patients accustomed to immunotherapy?
  • How reproducible and durable are these responses on a large scale?
  • How can the redistribution of the lymphocytes be addressed?  Will chemotherapy help here?
  • Is there value in combining a PI3Ki with immunotherapy in earlier stage disease?

All of these questions are being evaluated in the next phase of the GS-1101 clinical trials.  I was impressed with the progress and where Gilead are going with the compound.

There are some questions that remain in my mind though.  CLL and iNHL have an embarrassment of riches in pipeline agents at the moment, with several promising compounds in development.

The obvious rival to PI3K delta inhibitors are the bruton kinase inhibitors (BTK) such as Pharmacyclics/J&J’s ibrutinib (PCI-32765), which reported impressive data at ASH last December, followed up by new data at ASCO on the combination of ibrutinib with an approved CD20 antibody, ofatumumab.

This got me thinking…

1) If we assume that both agents are lucky enough to get approved by the FDA sometime in the near future, how will oncologists and hematologists decide which agent to give which patient?  Can patients be stratified in any way in order to define selection for treatment?

2) Is there any data on whether combining these agents together would be synergistic? (I don’t think so, yet)

3) If a PI3K-delta and a BTK inhibitor were synergistic preclinically, what are the chances emerging of a combination trial between the four companies involved in the development of GS-1101 and ibrutinib?  Sadly, a cynic would shake their head and say very low, but we need an answer on 2) from academic research before we get too excited.

4) What are the mechanisms of adaptive resistance in patients to both classes of agents in CLL and NHL?  If we know the answer to this critical question, then rational combinations could be investigated further.

5) Would combining GS-1101 with CD20 antibody immunotherapies such as rituximab and ofatumumab be an interesting approach to see if better response rates and outcomes will be achieved?  These are indeed being planned, along with a combination with bendamustine, another drug often used in relapsed/refractory NHL and CLL.

6) How will sequencing be important?  If a patient is eligible for either therapy, which one should be tried first?  This area is rather murky right now.

We’ve come a long way so far with both of these compounds, but there’s still an even longer way to go before we have some clarity on how they might change clinical practice and help improve outcomes for patients with NHL and CLL.

This is definitely an exciting area to watch out for, even if we have more questions than answers right now.

Here’s a quick update on the next conference I’m planning to attend in New York next week.  It’s hosted by the New York Academy of Sciences (NYAS) in their downtown New York headquarters by the World Trade Center, which has fantastic panoramic views of uptown Manhattan and Brooklyn from the 40th floor.  More importantantly though, judging by the last few meetings I’ve attended there on cancer metabolism and a most fascinating lecture on ink and tattoos from Carl Zimmer, it should be a very good event and well worth attending.

The latest conference is a two day affair on “Inositol Phospholipid Signaling in Physiology and Disease” otherwise known as the PI3K-AKT-mTOR pathway, which is a key process that is dysregulated in many cancers:

PI3K mTOR AKT Cancer Signaling Pathway Conference

The organizing committee of William Kerr (Suny), Christina Mitchell (Monash Univ) and Christian Rommel (Intellikine) have done an excellent job putting together a comprehensive program that covers a wide variety of related topics from both academia and industry across the globe.

I’m really looking forward not only to the science feast, but also to the networking opportunities to mix and mingle with some of the top researchers in the PI3K field, including Lew Cantley (Harvard), Neal Rosen (MSKCC), Bart Vanhaessebroeck (Barts, London) and David Solit (MSKCC) amongst many others.

For those of you interested in registering for this event, you can obtain a 15% discount when you click on the graphic or link above and enter the coupon code INOSITOL15 on checkout, as I’m delighted to say Icarus Consultants was invited to be one of the media partners for the event.

For those who cannot attend, I’ll post a short synopsis of the conference on PSB after the event later next week.  In the meantime, I hope to see you there!

error: Content is protected !!