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Bromodomain Inhibitors – an exciting new target in cancer research?

One of the interesting things about basic cancer research is that new targets emerge all the time, offering fresh opportunities for developing novel therapeutics in the quest for clinical improvement. While you see many companies chasing the same well established targets, often generating me-toos, sometimes serendipity favours the bold and the brave, as we recently saw with Pfizer’s development of crizotinib for ALK+ lung cancer.

So what’s new on the R&D front?

Bromodomain inhibition is a novel cancer target and one that I am looking forward to learning more about at forthcoming annual meeting of the American Association for Cancer Research (AACR) in Washington DC.

The plenary session on Monday April 8 on Epigenetic Targets in Cancer includes a presentation by James Bradner (Dana-Farber Cancer Institute) on Bromodomain Inhibition in Cancer.

What are BET bromodomains?

Although there are 47 bromodomain proteins, a subset of four proteins are associated specifically with the BET bromodomain, including a terminal (T) node:

  1. BRD2
  2. BRD3
  3. BRD4
  4. BRDT

These bromodomains are acetyl-lysine binding pockets that target bromodomain-containing proteins to histones and thereby affect chromatin structure and function. The binding of BET protein bromodomains to chromatin regulates gene expression. Whenever histones are involved, epigenetics are never far behind.

Thus in simple terms, it is now believed that targeting the binding of bromodomain and extra-terminal [BET] proteins to chromatin, it may be possible to regulate gene expression, and in particular, the transcription of key oncogenes such as MYC, which can lead to arresting of cell-cycle progression and apoptosis (programmed cell death).  In plain English, this means that cancer cells are selectively killed.

Some of the groups original preclinical work in this area was published in Nature a couple of years ago – it was ground breaking work because generally protein-protein interactions such as MYC are considered very difficult targets to drug, unlike tyrosine protein kinases (TKIs), which are more accessible. More recent work by Lin et al., (2012) in Cell elaborated on the significance of low and high MYC levels.

Since then, the research has moved into the translational and clinical space. Small molecule inhibition of BET is a drug development target of Cambridge, MA based Constellation Pharmaceuticals, who announced last September that they partnered with The Leukemia & Lymphoma Society to develop their novel BET for the treatment of hematologic malignancies.

Highlighting the significance of this work is the announcement in January this year (see Fierce Biotech’s piece for more details) is a $95M deal with Genentech, which includes a buyout option. I thought this was a smart move at the time, given the importance and solidity of the basic research findings. The venture funds invested in privately-held Constellation Pharmaceuticals clearly have an exit strategy in mind.

I am hoping that Dr Bradner’s AACR plenary presentation will discuss Constellation’s drug development pipeline.

What makes BET bromodomain inhibitors of even more interest as a potential target is the possibility that there may be biomarkers that will identify those patients most likely to respond to therapy. For those of you interested in a basic understanding of biomarkers, you can read more on Biotech Strategy Blog for an overview.

Preclinical research published by the group in the March 2013 edition of Cancer Discovery highlights how a genetic biomarker could be used to identify those cancer patients likely to respond to a new class of cancer drugs, BET Bromodomain Inhibitors.

MYC is overexpressed in many cancers but until recently, has largely been ignored as an ‘undruggable target’.  A rare malignant childhood cancer known as neuroblastoma, for example, is associated with the amplification of the MYCN gene and generally considered to be difficult to treat unless it is caught early and surgical resection is feasible. New work published in Cancer Discovery by Puissant et al., gives hope that therapeutic targeting with bromodain inhibitors might be a feasible strategy to pursue.

Recent research published in 2011 in the Proceedings of the National Academy of Science (PNAS) by Jennifer Mertz et al., at Constellation Pharmaceuticals showed that you could target MYC dependence in cancer by inhibiting BET bromodomains. They showed that:

“Small molecule inhibition of BET bromodomains leads to selective killing of tumor cells across a broad range of hematologic malignancies and in subsets of solid tumors.”

Fast forward to the work published in Cancer Discovery. Using high-throughput screening the researchers at Dana Farber found that amplification of the MYCN gene in neuroblastomas was sensitive to BET bromodomain inhibitors. Using cell lines with MYCN amplification and a mouse model of neuroblastoma, they showed that BET bromodomain inhibitors prolonged survival and had anti-tumor effects.

The Cancer Discovery abstract describes the significance of this work:

“Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new com- pound class with promising anticancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, show a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma.”

What does all this data mean?

It has long been known that MYC protein is likely oncogenic in some tumour types, including some hematologic cancers and paediatric neuroblastoma, but the challenge has finding ways to effectively target it at effective therapeutic levels. This new research has now moved forward the field sufficiently, such that not only have potential biomarkers of response been identified, but inhibitors are also in advanced preclinical development. This is an exciting new avenue of research that is well worth watching out for in the future.

References:

ResearchBlogging.orgFilippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W., Fedorov, O., Morse, E., Keates, T., Hickman, T., Felletar, I., Philpott, M., Munro, S., McKeown, M., Wang, Y., Christie, A., West, N., Cameron, M., Schwartz, B., Heightman, T., La Thangue, N., French, C., Wiest, O., Kung, A., Knapp, S., & Bradner, J. (2010). Selective inhibition of BET bromodomains Nature, 468 (7327), 1067–1073 DOI: 10.1038/nature09504

Puissant, A., Frumm, S., Alexe, G., Bassil, C., Qi, J., Chanthery, Y., Nekritz, E., Zeid, R., Gustafson, W., Greninger, P., Garnett, M., McDermott, U., Benes, C., Kung, A., Weiss, W., Bradner, J., & Stegmaier, K. (2013). Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition Cancer Discovery, 3 (3), 308–323 DOI: 10.1158/2159–8290.CD–12–0418

Lin, C., Lovén, J., Rahl, P., Paranal, R., Burge, C., Bradner, J., Lee, T., & Young, R. (2012). Transcriptional Amplification in Tumor Cells with Elevated c-Myc Cell, 151 (1), 56–67 DOI: 10.1016/j.cell.2012.08.026

Mertz, J., Conery, A., Bryant, B., Sandy, P., Balasubramanian, S., Mele, D., Bergeron, L., & Sims, R. (2011). Targeting MYC dependence in cancer by inhibiting BET bromodomains Proceedings of the National Academy of Sciences, 108 (40), 16669–16674 DOI: 10.1073/pnas.1108190108

Schnepp, R., & Maris, J. (2013). Targeting MYCN: A Good BET for Improving Neuroblastoma Therapy? Cancer Discovery, 3 (3), 255–257 DOI: 10.1158/2159–8290.CD–13–0018

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Will biomarkers revolutionalise treatment with tivozanib?

By on February 25, 2013

Following last weeks post on the phase III clinical data for tivozanib in advanced renal cell cancer (RCC), I thought it would be useful to provide an update on AVEO’s biomarker program.

I’m very excited about the work they are doing in this area and have been following them keenly since they first presented their initial work on myeloid cells in RCC at the AACR diagnostic conference back in 2010.  Since then, other companies have also published work in this field, including Regeneron, who also noticed the presence of myeloid cells in their work with aflibercept in glioblastoma.

Biomarkers have been very much a bête noire in angiogenesis research – we know that some patients respond well to therapy, but others do poorly and may actually be worse off.  The challenge has been finding a way to link biology with response in order to improve patient selection.  Genentech/Roche have laudably spent millions in their quest for biomarkers with bevacizumab (Avastin), with researchers clearly very frustrated at the confounding data presented at the 2011 ECCO meeting in Stockholm. Clearly, we have a long way to go in this field.

Murray Robinson, AVEO

Murray Robinson, Courtesy of AVEO

Last week I caught up with AVEO’s Murray Robinson (who is the Special Advisor to the CEO), to discuss the progress they are making on the biomarker front.

The recent ASCO GU meeting in Orlando highlighted very interesting data on a new biomarker they are researching, which involves a hypoxia gene signature in RCC (PDF download).

While this data is still preliminary at the moment, it is being tested prospectively in some ongoing trials in both renal and breast cancers.  Readouts are expected by the end of this year and may reveal some interesting findings.

PSB: Does the hypoxia biomarker in your poster at ASCO GU connect with the myeloid biomarker you presented back in Denver at AACR, or is this completely different?

Murray Robinson: This is one is independent of that, completely different, although as you can imagine we are looking at the myeloid biology in this same dataset. To put that to rest, we ran into some technical details, technical challenges on that. Remember when you are doing these trials, you only get the material you get, and you don’t always get the quality, and can’t go back and recut it.

We are really looking forward for the marker in this paper as well as that that myeloid work, to an ongoing study of a 100 patients mostly in the US, RCC – BATON (Biomarker Assessment of Tivozanib ONcology) study and we will get to take another look at this hypoxia biomarker, the myeloid biomarker and a few others that we are looking at. That study will mature soon, we are expecting probably sometime later this year.

PSB: Are these two biomarkers going to be practical in the future for community oncologists to use or is it going to be something that is a research tool do you think?

All of us are now applying high resolution molecular analysis to all of the tumors, all the TCGA work, whole genome transcriptome on things. As the field has done that, we have all been amazed and enlightened by the complexity within what the field used to call a single genotype.

We are all recognizing there are many molecular subsets. This of course was first elucidated 10 years ago in breast cancer. In breast cancer we are very comfortable with these idea, it’s not breast cancer, it’s ER+, or HER2 amplified or triple negative. And of course treatment assignment can be based on that, and we are even further refining those subsets. We haven’t that kind of resolution until recently with many of the other tumor types.

Let’s turn to renal cell carcinoma, (RCC) which is the subject of this work. We in the field have long considered clear cell renal carcinoma, which is 85% of RCC, to be a tumor type. However, as the field has begun to sequence and do profiling on many of these tumors, we have begun to recognize that it is in fact more complex than that.

In our poster, we first cited some great pioneering work by Dr Kim Rathmell down at UNC Chapel Hill where she really was one of the first to take a look at these subtypes of clear cell, and has reported now, and we excerpted one of her figures from a recent paper of hers on our poster. And she sees three major subtypes of clear cell kidney cancer. Two of those subtypes she has talked about before, and we won’t spend much more time talking today. They don’t seem to differentiate for a number of key biological features. A third type she has identified, and we also independently identified, is the subject of this work.

What we, and others, have recognized is that there are new, previously underappreciated, subtypes of clear cell carcinoma.  We focused on this one novel subtype, which Kim called Cluster 3, and we then applied some of our own bioinformatics platform to this, in which we have comprehensively charaterized tumors for key robust signatures.

We applied those key robust signatures that usually represent biology to this third tumor type.  We saw that there were a number of key features in which these tumors varied, this is about 15% of clear cell RCC, so it is a relatively small subset. We noticed in particular that one of the dominant differentiating features of this tumor was the expression of its hypoxia responsive genes.

We recognize there’s a different tumor type here, and that the tumor type is now low for a large signature that we have had for hypoxia, and we of course are thinking translationally, and in terms of molecular diagnostics as well.  We optimized to reduce that hypoxia gene signature to a nine gene signature and we optimized the ability to measure those genes often using single sections from clinical paraffin embedded material.

We are absolutely thinking about this biology and are looking toward to the development of a simple diagnostic test, if that were warranted.

We looked at that nine gene signature, quantified it then looked at its impact on response to tivozanib as well as sorafenib.

PSB: My understanding from looking at your poster in this particular subset with the hypoxic element is that some patients did better in response to tivozanib than others?

Murray Robinson: That is the observation that we made.

Our interest in looking at hypoxia in tivozanib is that hypoxia as we showed in one of our figures, that signature relates to the over-expresssion of key VEGF ligands, VEGFA, PLGF and VEGFC.

One hypothesis that we generated from these observations is that when the VEGF pathway is deregulated or overactive as it is in most of clear cell, then you are more likely to respond to a selective, potent VEGF pathway inhibitor like tivozanib. Conversely, then if you find a subtype that is not, the hypothesis is that it would not respond well.

We tested that in the study, and with the important caveat that we had 69 samples out of the total trial of 517 patients, then we looked at this subtype. Well, we predicted the subtype would represent about 15% of the total, so we went form 69 down to about 30 samples, then 15% of those I think we ended up with 4 of the low subtype in both [arms]. We all recognize those are pretty small numbers. We are really looking forward to the second study I mentioned to you.

PSB: You will still have to validate the results in a larger sample?

Murray Robinson: We think that would be prudent. We think it is difficult to make much out of 4 samples, however that is the amount that would be predicted. It is consistent with all the work that we have done previously. We are also certainly pleased that those 4 patients did not perform well on tivozanib, whereas in the remaining 85% of those patients, those patients did very well.

In fact median PFS of the high patients, representing 85% of the study population, was 18.3 months, which is very respectable progression free survival.

PSB: In other words you have a very good way upfront to potentially predict up front which patients might do well on tivozanib?

Murray Robinson: That was the hypothesis going into this, this was a prospectively designed hypothesis that we wrote up. It was not exploratory.

There is another point here that we’re pretty excited about. One thing we know about the field, that we didn’t 10 years ago, is that despite the original enthusiasm around the VEGF pathway as being a key angiogenesis inhibitor pathway, we all know the large amount of clinical data over the last 10 years with different VEGF pathway inhibitors has been disappointing.

I think there has been a lot of disappointment about the expectations about the VEGF inhibitors versus their performance. The VEGF pathway inhibitors are working, there are a number of indications there, but it certainly hasn’t been that universal broad-acting, cytotoxic agent that we all thought it was, would have been back in 1999.

The bigger question is can we use an understanding of the biology, an understanding of gene signatures, to better select patients in other indications? What we showed in this paper is that 85% of these patients have this VEGF deregulation signature and that is consistent with the fact that clear cell carcinoma actually exhibits robust single agent response to tivozanib and activity with other VEGF type agents.

We really are interested with the signature in expanding and using this as a biomarker outside of clear cell carcinoma, and we have now have done that. Those studies are in progress.

We did a survey of this hypoxia signature across multiple tumor types and made an observation that we are pretty excited about. That is, we found that the hypoxic signature is not as prevalent in those tumor types as it is in clear cell.

We did find that it was present in subsets of tumor types, and we particularly noted that in triple negative breast cancer (TNBC), the hypoxia gene signature is high in a high proportion of triple negative breast cancer.

That is interesting because there is some anecdotal or retrospective clinical data that suggests that VEGF pathway inhibitor agents may work a little bit better in triple negative breast cancer, a challenging tumor type with high unmet medical need.

That observation led to us starting a new phase 2 trial in breast cancer, the BATON-breast study that we started a few months ago. In that study, we will be looking at triple negative breast cancer and we are looking at a randomized phase 2, and we are looking at paclitaxel versus paclitaxel plus tivozanib. In that study we will be measuring the hypoxia biomarker signature.

We have started that and are planning on using a specific assay to look at those patients.

PSB: And finally, for the prospective renal trial with biomarkers when do you expect that to read out, is it anytime soon?

Murray Robinson: I would expect to look for that around the end of the year, recognizing that we don’t know when that’s going to mature, but second half of the year that is when we are expecting. We are looking forward to those results.

We think that there is a strong hypothesis for this and we are pleased in the TIV0-1 study that we saw data consistent with the hypothesis.

Some personal thoughts and additional insights… 

Before anyone gets in too much of a tizzy, note that the data reported at ASCO GU are preliminary findings in a small sample size with only a few (n=4) hypoxia low patients, as Dr Robinson fairly pointed out.  They need to be validated prospectively in a randomised controlled study to ensure that the initial findings are real and not a fluke. The good news, however, is that the consistent lack of response in these patients enabled the hypothesis to be tested further in new trials. It’s certainly a concept that worth testing.

We have known, or suspect, that VEGF inhibitors work in conditions of tumour hypoxia, but this is the first time I can recall anyone connecting the hypothesis to clinical response.  Assuming that the findings can be validated in the prospective trials – and a commercial assay developed in the future – then the ability to select patients with RCC who are more likely to respond to a VEGF inhibitor such as tivozanib would be most welcome.

Would other VEGF inhibitors need to show the same effect or would a class effect be assumed?  In my book, you can’t always assume that one biomarker for one drug will always translate to others without data.  In this study a significant effect was seen for tivozanib but not sorafenib based on the hypoxia biomarker.  We don’t know what the impact is with other VEGF inhibitors such as sunitinib, pazopanib, bevacizumab and axitinib. It will be most interesting to see what happens here, as the hypoxia biomarker made be a differentiating factor for tivozanib in the future.

The upside for a VEGF inhibitor in TNBC is potentially huge, much bigger than RCC.  What would drive this element though is not only positive data but also a way to predict and select which patients are more likely to respond.  Essentially, if the data is positive, it may well redefine a subset of the disease, much in the same way that CD117 (KIT) enabled GIST patients to be differentiated from other types of soft tissue sarcomas.  When you can do that, it makes matching treatment to patients a whole lot easier for clinicians and pathologists.

Update on KRAS in pancreatic cancer

Today, I’m heading off to The New York Academy of Sciences (NYAS) for an afternoon of lectures on pancreatic cancer.  It’s free for members and only $40 for non-members.  Previous 1-day and half day meetings I’ve attended at NYAS have been packed with information and very enjoyable.

The New York Academy of Sciences Pancreatic Cancer Meeting

Why am I interested in this meeting?

Well, aside from Icarus Consultants being one of the media partners for this worthy event, we like to support scientific causes that facilitate cancer research and the communication of the data.

We know that the standard of care may possibly be changing soon with the data from the nab-paclitaxel (Abraxane) due before the year end, but even if the median survival is doubled from 5-6 months with gemcitabine to 10-12 months with nab-paclitaxel, we still have a long way to go in overcoming both primary and acquired resistance to treatment.  Additional improvements in the future will likely come from targeted agents aimed at different oncogenes.  There is a lot of active research going on now to try and figure out what those targets are and how best to attack them effectively.

Scientifically, the event promises to be an interesting one – we know that KRAS plays an important role in resistance to treatment in this disease – so understanding how things work in tumorigenesis is crucial for potential new breakthroughs in this terrible disease.  There are two lectures on KRAS and another on autophagy that I am particularly keen on hearing.

David Tuveson (Cold Spring Harbor Laboratory) is also giving an overview of therapies in development based on their mouse model of pancreatic cancer, including a new target they are working on ie Connective Tissue Growth Factor (CTGF), which I confess is a new one for me!

If you’re going to the meeting, do introduce yourself and say hello!  It’s also not too late to register if you are in the NY Metro area. An online webinar is available for members who can’t make it to the live event.

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ASCO 2012 Update 2: Overcoming resistance in metastatic melanoma

By on June 29, 2012

Photo Credit: Sally Church Pharma Strategy BlogFollowing on from my preview of the 2012 American Society of Clinical Oncology (ASCO) meeting, I am now working through updates on some of the hot topics.

I’m delighted to announce The Chemical & Engineering News blog ‘The Haystack’, have published my second guest post on advances in metastatic melanoma.

This is a devastating disease that has seen very few advances over the last decade since the approval of dacarbazine (DTIC) until last year when the FDA approved two new therapies in vemurafenib (Zelboraf) for patients with the BRAFV600E mutation and ipilumumab (Yervoy), an immunotherapy that targets CTLA4.

Since then, we’ve realised that the inevitable happens – patients tumours become resistant to single agent TKI therapy because adaptive resistance pathways are activated and cross-talk with the MAPK kinase pathway often occurs.  The question of how we can improve on the encouraging results seen so far was explored in new trials in Chicago?

For those of you interested, you read my summary on The Haystack about the new developments in metastatic melanoma from ASCO, which includes dabrafenib, trametinib, anti-PD-1 and others.

For those who missed it, I also wrote a guest post about the ASCO 2012 data on overcoming resistance in non-small cell lung cancer.

May I take this opportunity to wish all my American readers a very enjoyable July 4th Independence Day weekend!

 

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Ribonucleases (RNase) – clinical applications for cancer therapy

By on May 1, 2012

This is the second post of a two-part mini series on RNases with Dr Laura Strong of Quintessence Biosciences.  If you haven’t yet read it, check out yesterday’s post, which focused on Ribonucleases (RNase) – what are they and why are they relevant to cancer?

Yesterday, we learned that RNases kill cancer cells by a novel mechanism – destruction of RNA – and may be synergistic with some chemotherapy agents.

In the second part of the mini-series, Laura is going to discuss Quintessence’s progress with moving QBI–139, their lead RNase compound, from precinical research to the clinic. This post focuses on how a small biotech company decided upon the relevant clinical targets they wanted to focus on and reported the initial findings at the American Association for Cancer Research (AACR) meeting last month.

What is the clinical plan for a broadly active agent without a marker?

We took QBI–139 into a first-in-human Phase I trial with the primary objective of understanding the safety profile of the drug in patients with solid tumors. While dose escalating continues, the trial should be complete this year.

In the meantime, we have been refining our strategy for the next stage of clinical development.  One of our challenges is the selection of tumor type because the drug showed broad efficacy in the xenograft models. After considering a variety of factors (including markets, competition, regulatory impacts and clinical trial designs), we narrowed our disease focus to non-small cell lung (NSCLC) and ovarian cancers. Despite having single agent activity, we anticipate advancing QBI–139 as part of a combination regimen with a standard of care drug. We have been gathering in vitro and in vivo data to support these approaches and we shared some of our in vitro results at the AACR 2012 annual meeting.

To select the drugs we would combine with QBI–139, the first, second and third line therapies in non-small cell lung and ovarian cancers were evaluated. The diseases are an interesting dichotomy because ovarian cancer is still largely treated as a single disease while non-small cell lung cancer (NSCLC) is transitioning to a collection of diseases divided largely by genetic mutations with some differences based on histology.

First line therapies in ovarian cancer are based on combinations of platinum drugs and taxanes. In contrast, second and third line therapies for ovarian cancer involve a variety of drugs (e.g. topotecan, gemcitabine, vinorelbine), which resulted in selection of cisplatin and docetaxel to explore in combination with QBI–139.

NSCLC patients with changes in EGFR, KRAS and ALK will be treated with targeted agents as first line therapy. The remainder, which is actually the majority, of NSCLC patients, will receive a first line therapy that often includes cisplatin as part of a combination regimen. {Editor’s Note: common NSCLC therapies typically include a platinum (eg cisplatin or carboplatin) and a taxane (eg paclitaxel or docetaxel), or other chemotherapy doublets (eg gemcitabine or pemetrexed with a platinum.)}

A cell viability assay was run to determine the concentration of each single agent that caused a half maximal effect (EC50). The combination studies were then run starting with each drug at the concentration of maximal effect.

Two graphs are provided as examples of the results. The ovarian cancer cell line OVCAR–3 (left) and the NSCLC cell line SK-MES–1 (right) were treated with QBI–139, cisplatin or a combination of the two drugs. The QBI–139 + cisplatin had an additive effect on the OVCAR–3 (ovarian cancer) cells and a synergistic effect on the SK-MES–1 (NSCLC) cells.

QBI-139 Quintessence Cell Viability

QBI-139 Cell Viability courtesy of Laura Strong, Quintessence

The combination index (CI) is then determined using the median effect analysis (This approach is sometimes referred to as the Chou Talalay combination index.). The CI values represent: additive effect (CI = 1), synergy (CI < 1) and antagonism (CI > 1).

What combinations have been evaluated so far?

The QBI–139 combinations showed synergy or additive effects against the ovarian cancer lines tested:

QBI–139 + Cisplatin:

  • SKOV–3 cells: CI=0.33
  • OVCAR–3 cells: CI=1

QBI–139 + Docetaxel:

  • SKOV–3 cells: CI=0.037
  • IGROV–1 cells: CI=0.05

The QBI–139 + cisplatin combination was synergistic against the non-small cell lung cancer lines tested:

  • A549 cells: CI=0.714
  • SK-MES–1 cells: CI=0.4

So what comes next for RNase therapies?

The discovery that naturally occurring RNases could be exploited for potent anti-cancer drugs has provided an alternative approach to RNA as a therapeutic target.  Our efforts have advanced a drug with broad activity in xenograft models into the clinic.  As we complete the Phase I trial, we are working to best position the drug for the next step on the path to delivering a new tool to help cancer patients.

 

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Ribonucleases (RNase) what are they and why are they relevant to cancer?

By on April 30, 2012

At the recent American Association for Cancer Research (AACR) meeting, I had the pleasure of meeting several interesting young scientists and physicians either in the poster halls or in various scientific sessions.  It seemed a great idea to encourage some of them to contribute some guess blog posts here on PSB.

Laura Strong, Quintessence Biosciences

Dr Laura Strong, Photo courtesy of Pieter Droppert, Biotech Strategy Blog

Amongst the people I met was Dr Laura Strong, President and COO of Quintessence Biosciences.

One of the joys of social media is that sometimes you can get to know people a little from online interactions before you actually meet them in real life, making it much easier to walk up and introduce yourself as a ‘warm’ rather than ‘cold’ contact from a conversational standpoint.  I’ve been following Laura (@scientre) for a while on Twitter and was keen to learn more about what her early stage biotech company does.

Quintessence Biosciences is, according to it’s website, “a biopharmaceutical company focused on development of novel protein-based therapeutics as anti-cancer agents. The Company’s products are based on the EVade™ Ribonuclease Technology which allows for the engineering of human proteins (ribonucleases) for the treatment of human diseases.”

Essentially, in plain English, this means that “The EVade™ Ribonucleases degrade ribonucleic acids (RNA), resulting in inhibition of protein synthesis and cell death.”

Source: Quintessence Biosciences

Laura was presenting a very interesting poster at the meeting, so I asked her if she was interested in writing a guest post about their work on RNases. She has most kindly agreed, so today and tomorrow we’re running a two-part mini series from Laura on RNases based on Quintessence’s work. For those interested in background research, you can check out more about the company here and also Laura’s blog, The Next Element.

RNases: From Concept to Clinic

At this year’s AACR Annual Meeting, I presented results from in vitro screening of combinations of our clinical stage ribonuclease (RNase). The theme of the meeting, Accelerating Science: Concept to Clinic, captures the serendipitous discovery that started on this course and subsequent development of this innovative and differentiated class of drugs.

Is RNA a good therapeutic target?

RNA has been a validated drug target for decades – from the discovery that various classes of antibiotics target ribosomal RNA to the more recent approaches using modified oligonucleotides to target specific RNA sequences.  Vitravene is an oligonucleotide designed to binds a critical cytomegalovirus (CMV) messenger RNA that was approved by the FDA to treat CMV retinitis in immunocompromised patients.  Recently a New Drug Application (NDA) was recently filed for another oligonucleotide drug, Kynamro (mipomersen sodium) that targets apolipoprotein-B to treat severe forms of familial hypercholesterolemia. These drugs have another feature in common: they do not target cancer.

In cancer drug development, the development of receptor tyrosine kinase inhibitors (TKIs) provides a potential roadmap for successful development of RNA-based therapies. While the early approved drugs, such as imatinib (targets bcr-abl to treat Philadelphia positive Chronic Myeloid Leukemia (CML)), provided significant benefit to patients, resistance via mutation in the ATP-binding pocket of the kinase domain has become a persistent problem in TKI therapy. This situation has prompted the development of second generation drugs (e.g. dasatinib and nilotinib for CML).

Another important lesson from TKI drug development is the clinical impact of targeting multiple and complementary aberrant signaling pathways. Even if the activity of one component of a pathway is blocked, there are often others that can compensate for the loss. In practice, this has led to development of pan-kinase inhibitors and to combining drugs in clinical trials based on the overlap of pathways. These results suggest that a single target approach may not have enough impact in targeting the RNA in cancer cells.

How do you go after multiple RNA targets?

One approach to target multiple RNA sequences inside a cell is to deliver multiple RNA drugs, such as modified oligonucleotides. Alnylam has taken this approach with their early clinical drug ALN-VSP. The drug uses small interfering RNA (siRNA), which are relatively short (1–22 base pair) RNA duplexes that inhibit messenger RNA once inside cells. In the case of ALN-VSP, two types of siRNA are included in a lipid nanoparticle. ALN-VSP targets two genes involved in liver cancer: kinesin spindle protein and vascular endothelial growth factor. The drug has completed a Phase I dose escalation study.

An alternative approach to attack multiple pieces of RNA in cancer cells is to use a human protein whose function is to degrade RNA, a ribonuclease (RNase). While this alternative may not be immediately obvious, serendipity played a role in bringing this concept to the clinic.  In the late 1980s, frog egg extracts were screened for in vitro anti-cancer activity with positive results. The active component turned out to be a frog RNase that is part of the RNase A family.

Professor Ronald Raines at the University of Wisconsin made the connection that bovine RNase A, the prototypical family member, was not toxic to cancer cells and identified a major difference between the frog and bovine RNases. The bovine RNase A binds very tightly to the ribonuclease inhibitor protein found in the cytosol of human cells while the frog RNase does not. Using this information, a variety of bovine RNase A variants were produced with diminished binding to the inhibitor and these RNases were cytotoxic to cancer cells in vitro.

Using the closest human homolog, human RNase I, we first tested the concept of whether certain RNase variants may have anti-tumor activity in preclinical cancer models in mice. Forty human RNase I variants were produced based on data from a crystal structure data of the bound RNase and inhibitor and then tested in xenograft models. The RNases showed a range of activity, highlighting that the activity of the RNase is based on evasion of ribonuclease inhibitor but there are other factors, such as internalization and pharmacokinetics that also contribute to efficacy.

QBI–139

We selected QBI–139 as our lead candidate because the drug had the greatest activity across the most tumor types, including breast, colorectal, non-small cell lung, ovarian, prostate and pancreatic cancers. QBI–139 maintains 95% sequence identity to the human RNase I. The efficacy of QBI–139 was similar to chemotherapies and targeted agents when tested in preclinical models. We also did not see the common toxicities associated with chemotherapy (e.g. myelosuppression, alopecia, etc.) in the efficacy models.

The example shown is a xenograft model of prostate cancer (DU145) comparing QBI–139 to the standard of care agent docetaxel as well as the frog RNase. On a once weekly schedule, QBI–139 provides equivalent efficacy as the other two agents with less toxicity. At this dose, QBI–139 did not cause death (as in the docetaxel arm) or weight loss (as in the frog RNase treatment arm).

Do check back PSB tomorrow for the second part of Laura’s synopsis on RNases, which discusses the clinical aspects and where Quintessence are going with this interesting and novel concept.

Highlights of AACR 2012 – Part 2

By on April 18, 2012

Yesterday, I mentioned that some of the best bits of this year’s American Association for Cancer Research (AACR) meeting were the numerous gems in the poster sessions.

Reuben Sierra, Ming Tsao's Lab (with permission)

One of the coolest such posters I came across was from Ming Tsao’s group.

Specifically, Rafael Sierra (see photo right) was hosting an excellent piece of research entitled: “Overcoming resistance to EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer.”

This is an area of much needed research and breakthroughs.

Why?

Well, at the ECCO meeting in Stockholm last September, Tom Lynch was discussing the role of one such EGFR therapy, cetuximab (Erbitux), in lung cancer and wearily declared prior to presenting a negative study,

“If ever there was a drug desperately needing a biomarker, it’s cetuximab”

because while some of the patients responded beautifully to the drug, many others didn’t and at that time, there was no way to determine upfront who might respond before treating.

This is clearly a waste of valuable resources and time because catch-all studies mean that the number of negative responses can balance out the positive responses in too heterogeneous a population.  That said, if you know what the potential target(s) or biomarker of response are, then you can select patients more precisely for a study and improve the subsequent overall response rates and OS advantage dramatically.

As Sierra et al., pointed out in their poster at AACR, we do know that:

“Patients that present amplification or activating mutations (L878R or exon 19 deletions) of EGFR, have higher response rates. Selection improved response rates from less than 10% to over 60–80%.”

This is very good progress, but how did their research take this concept further?

In this study, the group reported the preliminary findings from a complex study of genome-wide screenings on EGFR resistant cells to try and identify new genes that might mediate resistance and, importantly, be potentially druggable, unlike say, MYC. This would then offer new logical targets for combination therapies to be tested in the clinic in patients to determine if outcomes could be improved.

At the time of the poster presentation, the group had indeed identified a short list of potential candidates (not named as this would be available in a later publication). Conceptually though, this was an elegant study and I really liked the concept.

This morning, I was delighted to see a news snippet from the 3rd European Lung Cancer Conference in Geneva, Switzerland where the ESMO press release noted that Dr Tsao’s group performed:

“An exploratory analysis on the TORCH patient tumor samples that were available for analysis, looking for molecular biomarkers known to be potential predictors of benefit from EGFR inhibitors.”

Despite the biomarker analysis being pre-planned, however, only a third (36%) of samples were available for analysis. It is always harder to do retrospective mutation analysis on small sample sizes unless rigorously collected as per the BATTLE trials.

I’m looking forward to hearing what targets were identified in Drs Sierra and Ming’s research once published or presented in more detail at a future conference, as this may help us move the field forward in terms of rational combinations to either overcome resistance to EGFR therapy (other than the well known T790M mutation) or prevent resistance from developing early.

Now, that would be very cool and I do hope they alert us to the publication in due course – watch this space!

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Highlights of AACR 2012 – Part 1

By on April 17, 2012

The 2012 American Association for Cancer Research (AACR) meeting in Chicago was interesting for several reasons.  While there were no truly ground breaking data such as in previous years as with, for example:

  • vemurafenib in BRAFV600E melanoma
  • vismodegib in basal cell carcinoma (BCC)
  • crizotinib in ALK+ lung cancer

there were a lot of encouraging signs for the future.

What made the meeting exciting for me was the sheer number of new compounds emerging from late preclinical to early phase I – clearly companies are looking to restock their pipelines with the threat of major patent cliffs imminent.  Not everyone is chasing new compounds to license in!  The sheer breadth and depth of the pathways targeted by the new compounds took me a little by surprise.

It was clear from discussions with numerous new product people that while pipeline boards are starting to look a little healthier than of late, many of the new compounds are not yet public, but effort are being made to expedite these into the clinic too. Roche and Novartis have dominated the oncology landscape of the last few years but there were signs of resurgence from old stalwarts such as GSK, Lilly, Pfizer, Amgen and Merck. Such fierce competition is good to see.

Posters from Day 2 at AACR...

The small biotechs were also showcasing some interesting data and over the rest of this week, I’ll be highlighting some of the ones I liked and also explaining some of the new targets and biomarkers that caught my eye.

There was, however, a noticeable dearth of handouts and QR codes (for the PDFs) in the poster sessions this year, necessitating more requests for copies by email, hence the delay in covering the highlights post conference.

I’m pleased to say, however, that many presenters generously shared their poster offline and some of these will be discussed later this week.

Here are some of the topics I’m going to be covering in more detail:

  • Update on the PI3K-AKT-mTOR and RAS-RAF-MEK pathways
  • New targeted agents in late preclinical and phase I development
  • Review of the Science Policy session on regulatory and clinical challenges in new drug approvals
  • Update on new approaches in colorectal, prostate and lung cancers

Check back PSB daily this week for more detailed analyses and insights…

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American Association for Cancer Research Meeting 2012

By on March 31, 2012

Today marks the kick off for one of my favourite conferences on the oncology-hematology calendar, with the annual meeting of the American Association for Cancer Research (AACR) being held in Chicago.  It’s all about the science and basic research here, although there are clinical sessions, usually on strategy and early emerging phase I/II data.

Wifi is usually pretty good at the AACR annual meeting, although it can be more variable at the smaller meetings.  Like many attendees, wifi permitting, I’ll be tweeting from the conference and blogging some of the interesting highlights over the next few days.

For those interested, you can follow the Twitter chatter using the conference hashtag #aacr from attendees and non-attendees alike, by clicking on the widget below:

AACR have a strong web and social media presence as well as webcasts of sessions (some free, some paid), thanks to the sterling efforts of Ron Vitale and his web team, who do a fantastic job.

They also have iPad/iPhone or Android apps for those interested in looking at the program on the go and an abstract app as well.  After all, what use is a CD-rom of the abstracts if you’re running around McCormick place with a mobile device?  These days, most conferences, I don’t even take a laptop anymore, so a CD is pretty useless with an iPad or tablet!

One of my favourite tools last year was the video app, which offers selections of short interview of some of the presenters giving the highlights of their talks or findings.  This is a great idea for getting key points out on topics of interest.

Huge doorstop abstract/reference books, CD-Roms and flash keys/memory sticks will soon be a thing of the past.  I confess to being a huge big fan of reading the program as a PDF, so that it can be easily read and bookmarked in iBooks, on a plane, bus, or while running round the poster halls.

All of these digital tools are much more practical and user-friendly – tailored towards the typical on-the-go use by attendees and I sincerely wish more conferences would follow AACR’s lead and move over to the web 2.0 world in this fashion.

The conference runs through Wednesday, so do check back daily for the Twitter updates and we’ll be blogging anything interesting either here on PSB (follow @maverickny) or on Biotech Strategy Blog (follow Pieter Droppert, @3NT).

 

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On adaptive mechanisms of crizotinib resistance in ALK-positive lung cancer

By on March 23, 2012

One of the biggest challenges facing cancer research was aptly summarised by Levi Garraway and Pasi Jänne in this month’s Cancer Discovery journal:

“All successful cancer therapies are limited by the development of drug resistance. The increase in the understanding of the molecular and biochemical bases of drug efficacy has also facilitated studies elucidating the mechanism(s) of drug resistance.”

It will therefore come as no surprise to PSB readers that resistance occurs with two drugs approved by the FDA only last year; vemurafenib (BRAFV600E melanoma) and crizotinib (ALK+ lung cancer). We’ve discussed the development of resistance in melanoma here via several potential mechanisms in the past and potential strategies for overcoming them (eg MEK inhibitors), but what about lung cancer?

Two recently published papers have shed some new light on this topic. Doebele et al., (2012) and Katayama et al., (2012) both looked at mechanisms of resistance associated with ALK-rearranged lung cancers.

What did the research show?

Both of these papers were published in March, but in separate journals.

Doebele et al., (2012) examined mechanisms of ALK resistance in EML4-ALK–positive non-small cell lung cancer (NSCLC) patients who had progressed while on crizotinib patients (n=11). The essence of their findings were as follows:

  • Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. Two of the patients exhibited a novel mutation in the ALK domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro.
  • Two patients, including one with a resistance mutation, exhibited new onset ALK copy number gain (CNG).
  • One patient showed epidermal growth factor receptor (EGFR) mutant activity, without evidence of a persistent ALK gene rearrangement.
  • Two patients had a KRAS mutation, one of which occurred without evidence of persisting ALK gene rearrangement.
  • One patient showed the emergence of an ALK gene fusion–negative tumour with no identifiable alternate driver.
  • Two patients retained ALK positivity, with no identifiable resistance mechanism.

Meanwhile, Katayama et al., (2012) attempted to characterise acquired resistance, i.e. the adaptive resistance that occurs in response to treatment with a TKI. They also took biopsies from patients (n=18) with EML4-ALK–positive (NSCLC) patients who had progressed while on crizotinib. They found that in approximately a a quarter to a third of patients (22% to 36%) multiple mutations were found after sequencing of the ALK kinase domain exons. This resulted in amino-acid substitutions or insertions that are predicted to impair crizotinib binding. When this happens, the drug stops working and patients will relapse on therapy.

More specifically, there were:

  • Five patients (28%) had tumours with alterations in the ALK gene that were the underlying cause of the resistance.
  • There were four different somatic mutations within the ALK gene.
  • One case where the ALK gene was amplified.
  • One ALK mutation was highly resistant to all of the inhibitors examined.

In addition, they observed evidence of alternative mechanisms of resistance evolving, including activation of EGFR and KIT.

What do these results mean?

Firstly, it is striking that there are so many potential escape routes and mechanisms of adaptive resistance to crizotinib therapy.

Secondly, as Garraway and Jänne noted:

“Increased knowledge of drug resistance mechanisms will aid in the development of effective therapies for patients with cancer.”

However, while this is a true and accurate statement, I am left wondering how this might play out in clinical practice? By that, I mean how does a community medical oncologist, who sees the bulk of NSCLC patients go about incorporating this information? For now they can’t, as we are awaiting the results of numerous clinical trial readouts – hopefully there will be some at the annual ASCO meeting in June.

The sheer breadth of the heterogeneity also raises the issue of how will community doctors be able to process all this complex information and select patients for appropriate combination therapies based on numerous potential mechanisms of resistance. Biopsies aren’t always practical in these situations, but perhaps we may see the development of alternative methods of detection evolve in the future.

References:

ResearchBlogging.orgGarraway, L., & Janne, P. (2012). Circumventing Cancer Drug Resistance in the Era of Personalized Medicine Cancer Discovery, 2 (3), 214–226 DOI: 10.1158/2159–8290.CD–12–0012

Doebele, R., Pilling, A., Aisner, D., Kutateladze, T., Le, A., Weickhardt, A., Kondo, K., Linderman, D., Heasley, L., Franklin, W., Varella-Garcia, M., & Camidge, D. (2012). Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non-Small Cell Lung Cancer Clinical Cancer Research, 18 (5), 1472–1482 DOI: 10.1158/1078–0432.CCR–11–2906

Katayama, R., Shaw, A., Khan, T., Mino-Kenudson, M., Solomon, B., Halmos, B., Jessop, N., Wain, J., Yeo, A., Benes, C., Drew, L., Saeh, J., Crosby, K., Sequist, L., Iafrate, A., & Engelman, J. (2012). Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers Science Translational Medicine, 4 (120), 120–120 DOI: 10.1126/scitranslmed.3003316

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