We now turn our sights to targeted therapies and DNA Damage Repair (DDR). This is an important topic that has seen much focus in ovarian cancer of late and will likely see renewed interest in breast cancer at the forthcoming ASCO meeting next month. As we segue from one set of conference coverage to the next, there is inevitably going to be overlap, which is a good thing here as it helps with background and preparation in getting up to speed.
There is no doubt that DDR has had a bit of chequered history over the last decade, whether it be the spectacular (and sadly predictable) flop of Sanofi’s iniparib in triple negative breast cancer (TNBC), the negative ODAC incurred by AstraZeneca’s olaparib in ovarian cancer, or AbbVie’s more recent veliparib failures, to the much more positive events such as three PARP drugs now approved in different lines of therapy in ovarian cancer (olaparib, rucaparib and niraparib).
If ever there was a niche for the roller coaster ride that is oncology R&D, it has to be PARP inhibitors. There’s much more to DDR than just PARP though.
Indeed, there are multiple intriguing targets to explore and also the potential for combinations with cancer immunotherapy approaches that may yield encouraging results in the future.
Can we go beyond ovarian cancer into other tumour types and if so, which ones look encouraging and how woluld we go about exploring those idesa? What makes one approach more successful than another?
Here we explore the world of DDR through the lens one company’s approach and look at what they’ve done, where are they now and where they hope to be. It certainly makes for an intriguing and candid fireside chat.
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Dr James Gulley is Chief of the Genito-Urinary malignancies branch and Director of the Medical Oncology service at the National Cancer Institute (NCI) in the National Institutes of Health. He’s a world-leading GU cancer expert and at the forefront of pioneering research to make cancer immunotherapy work in prostate cancer.
We last spoke to him at ASCO 2015 (See post: The future of prostate cancer immunotherapy). You can listen to excerpts from this interview on Episode 4 of the Novel Targets podcast (See: The non-inflamed tumour show).
Almost two years on, and new research by Dr Gulley and colleagues from the NCI shows that the STING pathway may have an important role to play in prostate cancer immunotherapy. Activation of this pathway through a novel mechanism could turn a cold non-inflamed tumor into a more inflamed or hotter one in men with advanced prostate cancer. How cool is that?!
At the 2017 annual meeting of the American Association for Cancer Research (AACR) that was recently held in Washington DC, Dr Gulley graciously spoke to BSB about some of the novel trials that are underway at the NCI, with the aim of making cancer immunotherapy work in men with advanced prostate cancer.
Dr Jim Gulley, NCI at AACR17
This is the seventh expert interviews in our series from AACR17 where we explore the conundrum:
How does Dr Gulley plan to light the immune camp fire in prostate cancer?
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At the recent ASCO 2016 Genitourinary Cancers Symposium (ASCO GU) that took place in San Francisco the week before the JP Morgan Healthcare Conference (JPM), one of the noteworthy presentations was on a novel target for men with advanced prostate cancer.
While JPM may have been a “dud” for many, several companies did take the opportunity to update and discuss their corporate strategy going into 2016, which gave a surprising amount to comment on in our 3 blog posts from the meeting: JPM Day 1, JPM Day 2, JPM Day 3.
In this post we look at the “take homes” from the ASCO GU presentation, and what looks like it could be a new race to market.
It’s good to see novel targets for men with advanced prostate cancer, and potential new treatment options on the horizon!
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National Harbor, MD. Today was a busy day with the ASH abstracts coming out this morning, and some ground-breaking data that demanded an immediate #ASH15 preview post.
At the same time we’re here at SITC, and keeping an eye on the AACR-NCI-EORTC Molecular Targets meeting – it’s like three buses come at once!
So what happened at SITC today? In this post we’ve put a quick summary of some of the presentations we heard on Day 2 that stood out. Sometimes what’s most important is what people don’t say.
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With the launch of Episode 4 of the Novel Targets podcast today, I wanted to provide some more detailed background and a roadmap for this part of the journey for subscribers. There’s tremendous wealth of data now building up in several areas related to cancer immunotherapy and both interviewees, Drs Oliver Sartor (Tulane) and James Gulley (NCI), touched on many of them.
Thanks to Tom Gajewski’s exciting work, we can broadly think about different tumour types as inflamed (immunogenic) versus non-inflamed (non-immunogenic), which is a helpful starting point. Not all tumours thought to be responsive to immunotherapy will actually respond though, so we still have much work to do on the 70–80% of patients with solid tumours that don’t respond to these therapies.
Anyone who is interested can listen to the latest Novel Targets podcast.
The latest episode explores non-immunogenic tumours, using prostate cancer as an example. In the last third of the show, we do indeed talk about a promising new target that may have relevance not just to prostate cancer, but other tumour types too.
Listen to Episode 4 (open access thanks to our sponsors, Genentech)
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Have you ever sat in a freezing cold scientific session and been so engrossed in the compelling presentations that followed, you simply forgot to take notes? Not one. That actually happened to me at the American Association for Cancer Research (AACR) in Philadelphia this year in one of the many fringe sessions that I attended.
Reading Terminal Clock, Philadelphia
Granted, the hot topic of the conference was undoubtedly checkpoint inhibition, but I was anxious to escape to the comfort of some meaty and familiar basic and translational science, namely MYC. MYC is largely thought to be a difficult to target, even undruggable protein, and along with RAS and p53, represents a formidable challenge for cancer researchers. These three oncogenic proteins alone are probably responsible for more drug resistance developing and even death from cancer than any other proteins in a patient with advanced disease.
For cancer patients with advanced disease, the clock is ticking on time they have left.
Solve these three problems (MYC, RAS and p53) and we may have a shot at dramatically improving outcomes. As Dr Gerard Evans (Cambridge) noted:
“I think it’s fair to say that we don’t really know why interruption of any oncogenic signal actually kills cancer cells, but one of the reasons that we’re interested in MYC is because it seems to be a common downstream effector of many, maybe all cancers.”
Sure, the road to success is paved with an enormous graveyard of failures, just as metastatic melanoma was before checkpoint blockade came along, ironically. What I heard at AACR both inspired and filled me with greater confidence… we’re finally getting somewhere.
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It’s now time to turn our attention to genitourinary oncology and, in particular, prostate, renal and urothelial bladder cancers. This week brings this ASCO GU meeting (#GU15), which is being held in Orlando this year and began this morning.
There are quite a few interesting topics being covered here, particularly in the poster sessions over the next three days. Hopefully, 2015 will also bring more good news in this space as 2014 was a rather dismal one on several fronts!
We decided to highlight some of the most interesting abstracts on castrate resistant prostate cancer and urothelial bladder cancer in our latest conference preview.
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Since 2004, six new prostate cancer treatments have been approved for advanced prostate cancer: docetaxel (Taxotere), sipuleucel-T (Provenge), cabazitaxel (Jevtana), abiraterone (Zytiga), enzalutamide (Xtandi), radium-223 (Xofigo).
In the process, the competitive landscape has been radically transformed.
What we have seen more recently with the PREVAIL and COU-AA-302 data is a move to treat mildly symptomatic men earlier in metastatic disease prior to chemotherapy, thereby delaying disease progression, and in the case of enzalutamide, improving overall survival.
But how early can you go?
The focus of several companies looking to bring new prostate cancer drugs to market is now shifting from symptomatic metastatic castrate resistant prostate cancer (mCRPC) to earlier in the disease setting, i.e. asymptomatic M0 disease.
There are number of critical questions that need addressing, including:
- Should we treat men with metastatic (M0) castration-resistant prostate cancer (CRPC) who are asymptomatic?
- Will the treatments be able to demonstrate that taking them means men will live longer and feel better?
- Will there be a market for AR antagonists such as enzalutamide, ODM-201, and ARN-509 in M0 prostate cancer, where large randomised phase 3 trials are either underway or are planned?
Prof Tombal at ASCO GU 2013
During ASCO GU, I asked one of the leading thought leaders and researchers into this area for his candid perspective.
Subscribers to Premium Content can sign in or sign up in the box below to read what Professor Bertrand Tombal had to say on this topic – his answers may well surprise you.
It’s disappointing to learn from the ASCO 2013 GU symposium abstracts published today that Bristol Myers Squibb’s tyrosine kinase inhibitor, dasatinib (Sprycel), has failed in prostate cancer.
Dasatinib now joins a large graveyard of cancer drugs that showed promise in early clinical development in solid tumors, yet the data was not confirmed in a large scale randomized phase 3 trial.