The Uromigos Episode 129: Legends in GU Cancer Series—Phil Kantoff

Dr. Philip Kantoff discusses his career progression, highlights from his research, and prostate cancer.

Episode Transcript

Tom:
So, this is super cool. This is the next of our Legends series. I’m joined by Phil Kantoff who I see is a mentor of mine. I’m not sure if I told you that Phil, but I do.

Phil Kantoff:
That’s new to me. New to me.

Tom:
Phil, listen, do you want to introduce yourself super-fast and then Brian’s got a couple of the early questions?

Phil Kantoff:
Okay. I am a medical oncologist. I had been at the Dana-Farber for 28 years and specialized in GU oncology and became the head of the Lang Center at Dana-Farber, then the head of solid tumor oncology, and then about six and a half years ago I went down to Memorial Sloan Kettering to be the chairman of medicine.

And I left that at the end of June 2021 to become the chief executive officer of a company called Convergent Therapeutics. So, I’m thrilled to be here today with your Amigos, with Brian and Tom. Thank you.

Brian:
Thanks Phil. Thanks for joining. I consider you a mentor as well. So, you’re accumulating mentors, this podcast, or mentees …

Phil Kantoff:
We have a low bar here for mentorship. Mentorship from a distance. Thank you for including me.

Brian:
Yeah, thank you. So, I’ve known you for many years and remember started being at ASCO posters and seeing you buy posters and thinking, wow, there’s Phil Kantoff. He’s done so much in prostate cancer. And so, take us back sort of how’d you get involved in GU? How’d you get involved in prostate cancer, take a sort of the early days, and talk about that. Then maybe some of the early therapeutics you were involved in.

Phil Kantoff:
So, it was really serendipitous, I would say. So, after I finished my residency, I went down to the national institutes of health. And initially I was interested in cardiology and the PI that I was going to work at, work with at the NIH, took a sabbatical.

I had already committed to going down to the NIH and then found another lab, which was a lab in molecular hematology. And I spent four years there and I kind of switched my emphasis from wanting to get cardiologists to being an oncologist. And I applied for fellowships, and I landed at the Dana-Farber Cancer Institute.

To sort of abbreviate the story a little bit about halfway through my first year of fellowship, the president of the Dana-Farber Beruck Banastraruv who had won the Nobel prize for antigen presentation, Tom Fry, Bob Mayer, George Canellos, some of my mentors, asked me to stay on after my trip, because I was looking for jobs elsewhere, mostly thinking that I was going to be a wet lab genetics person, which was the dream since I was a kid.

So, I stayed on and there was an opening in the area of genital urinary oncology. There was nobody else doing it at the Dana-Farber at that time. So, it was really serendipity, it wasn’t by choice. I became an expert by title at that time in 1987.

Brian:
I love that.

Phil Kantoff:
I do remember if you’re the head of GU you at Dana-Farber Cancer Institute, they’re going to … People are going to call you up and ask for your opinion. People started to call me up and I would click the hold button on the phone, go over to the textbook, look it up and then give an answer. So that’s how it all started back in 1988. 89. GU at that time was testis cancer was a great area because Larry and George Basel and many others had made fantastic contributions, making it a very treatable and curable disease.

Bladder cancer, there was M vac and kidney cancer there was very little. And prostate cancer, this was pre-PSA. So, it was also a pretty bleak area. There was androgen deprivation therapy in the form of [inaudible 00:04:59] or LHRH analogs, which were just coming on. They were at that time daily, and then they became monthly injections. But chemotherapy and any of the therapy at that time was really had minimal impact on patients with prostate cancer.

Brian:
So, tell I’m embarrassed. I don’t know this LHRH was initially a daily injection?

Phil Kantoff:
It was initially a daily injection. The first publication back in 1980s was a daily injection. Yes.

Tom:
Phil what do you see as your early contributions from a development, a drug development perspective and how did you pick what you were going to do? Because you’ve said you wanted to go into wet lab work. Did you immediately go into clinical trials that translational oncology were going to start with that wet lab stuff?

Phil Kantoff:
Tom, the first thing I did was try to learn geo oncology. Become a so-called …

Tom:
I’m still trying …

Phil Kantoff:
Try to become a clinical expert. I did that by seeing a lot of patients at the beginning with the four diseases I mentioned. Fortunately writing reviews and then I was asked to join what was then CALGB, which was now Alliance and became one of the charter members of the GU committee.

I began to open up cooperative group trials. It wasn’t for a few years that I opened up my wet lab, went back to the wet lab and started my work there. I can come back to that later, but basically the beginning years were pretty lean for me. And it was really just trying to get up to speed and learn the diseases and begin to get involved in cooperative groups. It took a number of years before I did investigator-initiated trials, got involved in industry trials and got my wet lab closings.

Brian:
So, I have a follow-up question. How important is clinical expertise to being a clinical investigator? You said you spent a lot of the early years just developing disease-based knowledge. So, if you were advising a junior person who was debating, how much time do I spend in clinic versus clinical investigation? How important is that clinical expertise?

Phil Kantoff:
Well, I think the expertise is absolutely mandatory. You have to know the disease and have to roll up your sleeves at the beginning and really understand the disease, but you don’t want to get so caught up in clinical care after you get to the point of becoming an expert that you don’t have time to do investigation. I would say maximum amount of time if you want to be a clinical/translational investigator spent in the clinic is two days. That’s my opinion.

I don’t know how you guys feel about it, but that gives you … With two days in the clinic that carries over to another probably half day, and that leaves you with two and a half days to do investigative work. That’s my opinion. That’s what I’ve advised people. And over the course of my career, I cut back more and more my clinical activity to spend more time as an investigator.

I think it’s really important also to begin to think about writing grants early on, and whether it be K awards, clinical or laboratory, beginning to get industry funding. So, I think that’s really an early move to transition from the point of being a clinical expert in a particular disease area, to becoming an investigator.

Tom:
Phil when you look back at your career where there’s some breakthrough moments that really accelerated your academic progress and what were they?

Phil Kantoff:
Well, actually one of the most exciting times that I had was even before I did my fellowship, when I did my laboratory fellowships at the NIH, when I was involved in developing retroviral vectors as vectors for gene transfer.

I remember doing experiments when I got the results that I was … This was a moment that I will remember the rest of my life, the ability to transfer genes into hematopoietic stem cells and developing a blot that showed that we had successfully transferred genes into hematopoietic stem cells, ultimately transferring adenosine deaminate gene into adenosine deaminate deficient cell lines, T cells, and making them more competent.

Those were exciting moments in my early career, and I look back at that and say that those were some of the greatest moments of when you actually see those results in front of you.

Then the next sort of aha moment in my career, I think was actually years later when I was at the Dana-Farber and I had opened my wet lab, I had read an article by the famous geneticists, Tom Caskey, who described variations in the androgen receptor in the internal part of the gene, where there was a highly variable CAG repeat segment.

And he noted that there was a lot of variability from X chromosome to X chromosome, and Evelyn Barrack, who was then a Johns Hopkins made the observation that African-American men had fewer CAG repeats and speculated that perhaps having fewer of these repeats were the reason why African-American prostate cancer was more prevalent and more aggressive.

And then I read another article about … It was a basic science study that looked at the trans activating ability of the androgen receptor, depending upon how many CAG repeats it had and what they learned in that study was that if you had fewer CAG repeats, the transact debating ability, the transcriptional activity of the antrum receptor was greater.

So that was like an aha moment to me and I went to my colleague Miles Brown, and who’s a fantastic scientist at Dana-Farber, and we sat and talked about it for a while. And that’s when I opened the door to epidemiology in my discussions with Miles, we said, there’s a co there are cohorts at Harvard, the physician’s health study, the health professional follow-up study, where they’ve collected samples on patients and follow patients for many years.

And I said, at that time, maybe if we looked at a cohort of, of men with prostate cancer, without prostate cancer and measured their CAG repeat length in their interim receptors, we might find some difference. So, I approached my colleagues at the Harvard School of Public Health at that time, Mayor Stanford edgy of Nucci.

And they said, we have these samples, but we don’t have DNA. We don’t have any germline DNA. And I said, no problem. I’ll make the germline DNA and I’ll do the study.

And we went ahead and developed an essay, which in retrospect is, is, is, is pretty amazing that it took us about six months to analyze one polymorphism in one gene where you could do that experiment on hundreds of genes within a day now in hundreds of patients. But at that time doing single gene polymorphisms was where we were at.

That was our ability to do it. And we did demonstrate that in that study of over a thousand men with, and without prostate cancer, that if you had fewer CAG repeats in the end receptive germline, you were more susceptible to developing prostate cancer and more and more susceptive to developing aggressive prostate cancer.

That was a very exciting moment for me. Subsequently there have been mixed studies and part of that I think is due to the fact that the definition of prostate cancer has really changed as you know, with the use of the PSA where real prostate cancer was diluted with PSA detected prostate cancer, low grade prostate cancer. And some of the studies that were done more recently failed to show a relationship within the CAG repeat and aggressive prostate cancer, excuse me.

But nonetheless I to this day think there is something about it and there’s some truth to it, but it may be related to what I would say, real prostate cancer rather than the dilutional effect of in the PSA era. So that was early on. I’m sorry, go ahead.

Brian:
No, go ahead. I was going to ask about clinical stuff, if you want to finish that thought.

Phil Kantoff:
Sure. Yep. We can move on to clinical stuff. I was mostly involved in cooperative group studies and the area of prostate cancer clinically was pretty bleak in the 1990s. I had done a phase one study phase, one phase, two of infusional mindless antrum in prostate cancer. And there was some activity we published it and then that was brought to CALGB and we conducted a randomized study of mitis antrum versus a steroid in men with advanced castration resistant prostate cancer.

Ian Tanic at that time did a similar study. There was an improvement in quality of life and pain control in both studies and that led to the approval of a drug Brenda’s Antron, which had no impact on survival, but impacted on quality of life on pain control.

And that became a standard treatment for a number of years until Docetaxel came around in the early 2000, around 2003. And that’s where the field stood for the next eight years. And then as you all know, there’s had been an explosion of therapies in the 2010 and beyond era.

Tom:
Phil, you also went on to look at a pharmaceutical trial you led in [inaudible 00:17:01] study, which was in the new in journal. What is your feeling on your balance between the pharmaceutical industry and investigator-initiated trials and what have you learned from that process?

Phil Kantoff:
That’s a good question. I’ve always been a big advocate of investigator-initiated trials, but I think it’s important for young investigators, junior investigators to get involved with pharma because that’s and in biotech because that’s where drugs are most frequently created.

And even when you do investigator-initiated trials, as you know, you’re working with biotech or a pharmer with, for the drugs, although they’re not those trials are not as well funded, I’ve been fortunate to work in institutions where I’ve able to get funding to do investigator-initiated trials.

So, I think as both of you know and both of you have been incredibly successful is balancing between investigator-initiated trials and pharmaceutical sponsored trials where you guys have been on steering committees and guided pharma to the right type of trial. So, I don’t think the two are mutually exclusive.

I think both are important. The key thing with investigator-initiated trials is coming up with the right question and being able to answer a question with the trial, doing good biomarker studies along with it.

And the key thing with pharma studies is to get involved in the scientific advisory boards, get known in the field as you guys have extremely successfully, and lead trials. I think it’s very rewarding to lead a trial that is ultimately published in the new in journal or Atlanta or in JAMA. That is a breakthrough for patients with cancer.

Tom:
It’s often more satisfying to do an investigator-initiated trial. You lead it from the beginning, get it off the ground. It’s a lot harder work. It takes a lot longer. It often publishes less well. It’s often not practice changing.

I think it’s an area where we learn our craft, in my opinion, where the academic credit of these trials and the pharmaceutical trials is quite complicated. What’s your feeling on the current distribution of academic credit and how it’s balanced between pharma and investigator-initiated trials?

Phil Kantoff:
It’s a complex question Tom. I think that pharma wants to utilize individuals with great name recognition to lead trials. And there’s less of an opportunity at least initially in people’s careers to lead those big trials that lead to greater notoriety. I’m not an expert on how these are distributed, but I’ve seen people make decisions about them.

And I think at times it’s not exactly what I would say is fair, but you know, it serves pharmer well to have the household names as first authors or last authors on papers because they receive more attention.

Getting back to investigator-initiated trials. I think they’re really important, but the important thing to remember, I think, is if you’re going to do an investigator-initiated trial, you need to come up with an answer. You need to come up with either a biological answer or a clinical answer. If at the end of the day, it’s a what did I just do? What did I spend all my resources and time on? I didn’t get an answer.

You know, that’s a problem. So, think it through, because as you said, Tom, an enormous expenditure of energy to do these trials. So, my advice is just be very careful, pick the right questions, make sure you pick the right patients, the right setting, do the biomarker studies, make sure at the end of the day, you can come up with an answer.

Brian:
Phil, I want to go back to disease-based. Do you think we’ve started tapped out hormonal therapy in prostate cancer? I mean, where do we go from here? It seems like we’ve sort of inhibited that access to a maximum degree. Do you do agree with that? Or where do you think it’s going?

Phil Kantoff:
Yes and no. I do think people die with prostate cancer of maybe not androgen driven disease, but androgen receptor driven disease. There are some people who die of AR negative disease, neuroendocrine, prostate cancer, but I think even to this day, it’s the minority patients. And so, I do think that the androgen receptor and the androgen receptor signaling pathway is still important, whether we can develop therapeutics, whether they’d need be degraders or other strategies that deal with androgen signaling, I would not abandon it at this point.

I think there’s still more room, whether we can develop drugs that are successful remains to be seen. Having said that, I think there are other pathways that as you know, are important. I think the DNA repair pathways are important subsets of patients. I think PI three kinase signaling pathway is important. So, I think we need to diversify as we have. We haven’t really hit any home runs yet, but I think there’s still some room Brian in dealing with androgen signaling. So, I would not [inaudible 00:23:17] at this point.

Tom:
The first time I came to Dana-Farber to meet you, I met Jonathan Rosenberg and then Chris Sweeney and then Tony Tewari, and a whole string of well-known names who were all developing in their careers at the time. Maybe it was 10 years ago, might’ve even dare I say, it’d be longer. How did you bring such a great group of people together and manage them to play nicely in the sand pit and what leadership skills are required to develop that teamwork?

Phil Kantoff:
Right. Well, thanks for that question, Tom. I consider one of the things that I’m most proud of is the people who have come through and had successful careers and you just named a few. I would say that there are two groups of people.

There are the clinical investigators, but in addition, there were a bunch of laboratory-based investigators who said, I want to be part of this GU thing, because a good home to be in, to name a few Bill Sellers, Levi Garraway, Todd Gollob. On the laboratory side, Bill Hahn, Phil Febo. On the clinical side you named a few fantastic people. There’s William Mo, Dan George, Tim Gilligan. I’m missing a bunch of people, but what I’m proud of in that regard is creating environment where people are nurtured, connected.

At a certain point in my career, I put my ego aside and I said, it’s more important to develop other people because ultimately, I’ll be measured by how successful my program is, rather than my individual accomplishments. That that was a choice I made. I played in my own sandbox with things that I like to do, but I spent a lot of time trying to nurture the careers of others so that they became independent and were successful.

We just mentioned that a bunch of people who have gone on to be incredibly successful. Now, having said that being at a place like Dana-Farber or Memorial Sloan Kettering, or the institutions that you guys are at, there’s a fantastic feeder program of young talent. So, we had a fantastic fellowship program, both at Dana-Farber and at Memorial Sloan Kettering that fed into our programs and we’re the stars of tomorrow.

When these individuals see a nurturing environment, see an environment where there’s a track record of developing younger faculty, junior faculty, people are attracted to that, whether they be laboratory investigators or clinical investigators. So, thank you for that question.

Brian:
Phil I just have one last disease-based question. Do you think distant metastatic prostate cancer is curable in 2021? And if so, what percent do you think are ultimately curable?

Phil Kantoff:
Well, there has always been a small fraction of patients that we’ve treated with either androgen deprivation therapy, or with chemotherapy who were cured. It’s a small fraction, it’s probably in the single digits, but you know that they always existed because they had an incredible dependence on a particular pathway or a particular gene.

I think we’ve come a good ways in 2021 from where we were 10 years ago. I still think that a cure of advanced prostate cancer in a significant proportion of patients is still elusive.

I think we’re going to get there. I think it’s going to take multimodality therapy, but I think we’re still dealing with a small fraction of patients under 10% of patients who are long-term survivors in whom you can give their testosterone’s back, and they remain disease free. I’d love to hear your opinions on it, but that’s my feeling right now. I hope sincerely the next few years with developing therapies we’re going to do better.

Tom:
Phil at the end of these sessions we tend to have a quick fire round of questions that tend to be one- or two-word answers. Brian, do you want to kick off first?

Brian:
Sure. Phil, tell us the year and subject of your very first publication.

Phil Kantoff:
Like 19 …

Brian:
I don’t have your CV in front of me so you can make it up.

Phil Kantoff:
I’m going to guess around 1977, 78. And it was when I was at Brown University and studying tight binding inhibitors, an enzyme paper. Don’t ask me the specifics at this point.

Tom:
Okay. Phil David Bowie or Bruce Springsteen?

Phil Kantoff:
I’m going to go with David Bowie.

Brian:
Nice.

Tom:
I think so.

Brian:
What would you have been if not a physician?

Phil Kantoff:
A lead guitarist in a rock and roll band. Every time …

Brian:
Is this realistic or?

Tom:
Mohammed Ali or Michael Jordan?

Phil Kantoff:
Michael Jordan.

Brian:
Favorite location you’ve ever given a talk?

Phil Kantoff:
In Tom Pals’ hometown. I love London. I love Europe. I also, I would say number two would be in a variety of places in Italy, including Florence.

Tom:
Discovery of penicillin or the moon landings?

Phil Kantoff:
Discovery of penicillin.

Tom:
Yeah. One last one from me. I remember you as a martini drinker. How do you like your martinis prepared?

Phil Kantoff:
I haven’t had a martini in a bit, but I do like them dirty. And vodka Martinez straight up. I’d love to invite you guys to Martha’s Vineyard to join me and have a couple Martinez with me.

Brian:
Absolutely

Tom:
Phil, that’s fantastic. Listen, this has been terrific. Thanks so much for your time. We look forward to seeing you soon and we thank you again.

Phil Kantoff:
It was a pleasure guys. Keep up the great work you’re doing.