At the recent Triple (EORTC-NCI-AACR) and ASH meetings, Blueprint Medicines (Cambridge, MA) presented data on some of their targeted compounds in early clinical development including data in KIT, PDGFα and FGFR4 driven cancers.
While many observers attention is currently distracted on cancer immunotherapies, let’s not take our eye off the ball and forget that when we do find driver oncogenes in rare tumours, the activity of TKIs can still be superior in these situations and offer exquisite sensitivity, leading to exceptional responses.
Here, we take stock with a look what Blueprint are doing, where they’re going and also offer some perspectives from senior company executives, whom we interviewed last month.
Which reminds me, someone recently asked why we do so many interviews, “You do a prodigious amount of interviews on BSB, why is that?”
The answer is very simple – to learn faster and share that knowledge with other like minded souls. Charlie Ambler, author of Daily Zen, sums it up well in an essay about Talk Less:
“In Zen tradition, I’d like the kill the Buddha that is Lao Tzu and revise his ancient saying. It’s not that those who talk don’t know and those who know don’t talk— it’s that talking often inhibits us from knowing.”
Thus, the corollary here is that if you undertake interviews with scientists and researchers regularly then you have the pleasure of talking less – the person in the hotseat naturally talks more – and you learn faster.
What’s not to like? We all learn different things depending on our perspective and knowledge base. Sometimes, I even find re-reading old interviews a year or so later while preparing for a new one a related topic teaches me something new I didn’t see or realise before, simply because my own understanding has improved. Hopefully that is also true for subscribers!
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ASH16 in San Diego
Today we resume our coverage from the recent American Society of Hematology (ASH16) annual meeting with a look at some fascinating and highly compelling science that was presented in an obscure and hard to find tiny hall in San Diego.
This story is also about how a small biotech company that many casual observers may not even be aware of, is taking advantage of advances recent research to grab a clinical lead in a very specialised field in oncology that may yield a novel approach worthy of taking notice of..
Genomics is increasingly becoming a core element of cancer research. Think of it as the alphabet soup of molecular biology concerned with the structure, function, evolution, and mapping of genomes.
Once we understand and identify the genomic landscape in health and diseases such as cancer, it allows numerous platforms to evolve whereby those unique differences can be identified (as driver vs. passenger mutations, for example), explored in depth, and later key ones targeted with therapeutics. Inevitably, there are many ways to do this.
Much of the focus in genomics has been on DNA, but what about RNA?
RNA is important because a mistake – even a single nucleotide – can be devastating to the cell, and a reliable, repeatable method of RNA processing is necessary to ensure cell survival. Mis-splicing can thus lead to the development of new point mutations and genomic instability deep in the cell nucleus, potentially causing the evolution of certain cancers.
Paradoxically, these aberrations also offer novel therapeutic targets – but are they druggable?
What we are exploring here is a completely different approach, both in terms of how a fledgling company is funded and also the type of research that is conducted.
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HI Koko Crater Flowers
Over the last week or so, we’ve received a lot of questions on the following topics relating to women’s cancers in breast and ovarian carcinomas:
- APHINITY impact – pertuzumab and neratinib
- PARPs in ovarian cancer – niraparib, rucaparib and olaparib
- Seattle Genetics and Immunomedics
So this is probably a good time for a February BSB Reader Q&A post on the hot topics of the moment in cancer research.
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The huge pile of interesting scientific papers yet to be read seems to breed overnight and one constantly feels like they’re 2,000 articles behind, even with spending Friday mornings attacking them with gusto.
This was as true in my PhD days as it is now. For a scientist, these represent a lifeline and an important necessity, rather than a luxury.
In the last journal club posting we covered some hot topics in cancer immunotherapy, so this one covers a very different topic, namely targeted therapies.
It’s a good time for a new journal club post, where we tackle some of the recent published literature in oncology and highlight some important new findings that could have an impact on cancer research and development.
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Much of the focus in multiple myeloma over the last decade has focused on two key drug classes – proteasome inhibitors and IMiDs – with some recent approvals for monoclonal antibodies targeting key proteins on the surface of malignant myeloma cells such as CD38.
#ASH16 in San Diego
Combinations of these core therapies have lead to a noticeable improvement in outcomes for people living with the disease – from 3-4 years over a decade ago to now approaching 10 years post diagnosis.
If we want to continuously beat the status quo and improve on the chronicity, however, it is likely that several things will need to happen:
- Better understand mechanisms of resistance that induce relapse
- Develop predictive biomarkers of response
- Identify novel therapeutic targets
Here. we focus on the latest preclinical findings that were recently presented at the American Society of Hematology (ASH) in San Diego and explore where the future might be headed in this disease.
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As we move from monotherapies to combinations in the immuno-oncology space, we start to see some intriguing ideas being explored from additional checkpoints to vaccines to neoantigens to immune agonists to oncolytic viruses. There are numerous ways to evaluate how to boost or jumpstart more immune cells upfront in the hope of seeing better efficacy.
One way to do this is to better understand the tumour microenvironment.
Wall of people at ASH16 in San Diego
If we know what’s wrong under the hood, we might be better able to make the immune system get going… more gas, faulty starter motor, dead battery, loose wire, broken fan belt? All these things and more might be a problem so you can see that diagnosing the issue up from from basic and translational work might be instructive for clinical trials.
If you don’t know what problem you’re trying to fix or repair then you might as well be throwing mud at the wall. Just as we don’t expect a car mechanic to suggest changing the battery or starter-motor without first diagnosing the issue, so understanding the tumour microenvironment in each different cancer or disease might also be a helpful strategy.
At the recent American Society of Hematology annual meeting (#ASH16), there was a fascinating sceintifc workshop that focused on this very concept – what’s going on under the hood and how do we go about fixing it?
Here we explore these ideas via an interview with a thought leader and specialist in the field. What he had to say was very interesting and candid indeed.
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Today we continue the second of a two part interview with a global thought leader who is also a scientist-clinician and well versed in cancer research as well as clinical trials.
Old Town Hall, Munchen
We explore how we can do clinical trials better in order to learn via a more rigorous process what works, what doesn’t, and why. After all, we we don’t know why certain approaches didn’t work or what the mechanisms of resistance are, how can we possibly improve?
Randomness is not necessarily a good thing in clinical research, especially if you don’t know what target you’re actually trying to hit!
If you missed the first part of this latest KOL interview and want to catch up then you can find it here (Link).
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Two of the most intriguing developments in cancer research over the last 5 years have been checkpoint blockade and CAR T cell therapies. There’s no doubt that they work – in some patients – or that toxicities can be challenging to manage at times, but what has been very interesting to me has been physician reactions to the rise of immunotherapies.
There has been much noise about biomarkers, including whether they work or not in this niche, as well as how do we go about selecting patients for therapies and combinations?
Ultimately, immunotherapies will be no different from targeted therapies in that we need to better understand the underlying biology in order to move forward beyond the low hanging fruit and figure out how we can best select appropriate therapy for each individual based on their particular characteristics.
The worry that many researchers have is that we could end up making the same mistakes with immunotherapies as targeted therapies, i.e. treat them in a broad fashion akin to throwing mud at the wall. Indeed, some companies are already doing this, much to the consternation of the research community.
So how do we go about doing things better and thinking more strategically about what needs to be done?
Up next is the first in a two-part interview series with a global thought leader who is a scientist-clinician with expertise in both immunology and oncogenic pathways. What does he have to say about where we are now and importantly, what does the future hold?
This is the penultimate article in our coverage from the Triple meeting in Munich, held in November 2016.
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At the recent 2016 San Antonio Breast Cancer Symposium (SABCS16), Cascadian Therapeutics (NASDAQ: CASC) presented a poster (Abstract #P4–21–01) on:
“Efficacy Results of a Phase 1b Study of Tucatinib (ONT–380), an Oral HER2-Specific Inhibitor, in Combination With Capecitabine and Trastuzumab in HER2+ Metastatic Breast Cancer, Including Patients with Brain Metastases.”
Tucatinib is an oral tyrosine kinase inhibitor that is highly selective for HER2.
Cascadian’s tucatinib poster at #SABCS16
We’ve seen several new treatments approved for HER2 positive breast cancers in recent years including four targeted treatments: trastuzumab, pertuzumab, lapatinib and T-DM1.
Other companies such as Puma Biotech (NASDAQ: PBYI) also have oral TKIs in development. Puma’s drug, neratinib has, however been shown to have a high incidence of grade 3+ diarrhea, raising questions about its tolerance.
At SABCS16 (Abstract P02–11–03), the company presented the interim analysis of an open-label, multicenter phase 2 trial, which explored their compound:
“Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC).”
There has been a lot of interest and controversy in this space, so it’s time to take a look at the latest events in HER2+ breast cancer and consider the ramifications since there are a number of new developments that are well worth following, including neratinib (Puma Biotech) and pertuzumab (Genentech).
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San Francisco: In the final post of the week, it’s time to focus on some of the interesting concepts and early ideas being explored in GI tumours such as pancreatic and colorectal carcinomas.
Gems from the Poster Hall or what Dog Drug Heaven really looks like?
Despite the image implied by the used poster bins (right), there were actually several encouraging signs from emerging IO approaches as well as some surprising results that lead to some compounds – or at least some indications – going off to dog drug heaven.
There were also some salutory lessons to be learned in terms of understanding biomarkers and useful these can be.
After years of incremental improvements with targeted therapies, it’s time to look at whether some immunotherapy combinations can make an impact in what is known as cold tumours.
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