Oncology Central

Tamoxifen, SERMs and sustainable medicine: an interview with V. Craig Jordan & Balkees Abderrahman

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Roshaine Wijayatunga (Senior Editor: Oncology): We are here at the American Society of Clinical Oncology Annual Meeting (ASCO, 1–5 June 2018, IL, USA) with Professor V. Craig Jordan from UT MD Anderson Cancer Center (TX, USA) and Balkees Abderrahman from UT MD Anderson Cancer Center and the University of Leeds (West Yorkshire, UK).

  1. V. Craig Jordan, can you tell us a little bit about yourself and your journey in oncology and oncology research to date?

V. Craig Jordan: Well, it is a long story but we will do the short version. I was an individual, who simply had a passion for chemistry. My mother had let me convert my bedroom into my chemistry laboratory at the age of 11! I was blowing things up. One time, I nearly killed myself with the chlorine gas that I had made. Curtains were set on fire – but my mother would say, ’At least we know where he is!’ I was passionate about chemistry, I also liked languages (French), and geography. But, I wasn’t terribly good at school. I got into the sixth form and did chemistry and zoology as I wasn’t interested in doing anything else. I had to do O-level physics because I was going to be a technician in ICI Pharmaceuticals, (now AstraZeneca, Cambridge, UK). But once I went into the sixth form, I found that I could teach university levels biochemistry to other boys at lunch breaks. The people I had taught went on to medical school!

My biology master and school’s career master, Mr. Bescoby, told my parents that I have the promise to go to university and succeed. The University of Leeds gave me my one chance to launch myself to the real world. I had one interview and they gave me an offer. Since I hadn’t done A-level physics, I had to do a 4-year course. I did extra chemistry and biochemistry, and got a PhD with a Medical Research Council Scholarship on failed contraceptives. My original PhD was supposed to be the crystallization of the oestrogen receptor with an oestrogen and an anti-oestrogen, to find out what it looks like; the mechanism of action of a drug, its pharmacology. But, nobody did it for the next 30 years, so I realized very early on that it was not going to happen. I quickly pivoted and started focusing on the structure–function relationships of anti-oestrogens. I did a post-doc at the Worcester Foundation for Experimental Biology (MA, USA)- the home of the oral contraceptive, because my PhD was on failed contraception.

When I went to this epicenter in the world in Massachusetts, the man that I was supposed to work with wasn’t there when I arrived! He wished me luck and told me I could do anything I liked – this is how fate and chance takes really hold! It’s like the movie Sliding Doors. My external examiner for my PhD happened to be Arthur Walpole, Head of the Fertility Control Program at ICI Pharmaceuticals (now AstraZeneca). They had a failed contraceptive; an anti-oestrogen termed ICI 46, 474, so I phoned him up and said, “If oestrogen fuels breast cancer growth then an anti-oestrogen like ICI 46, 474 could potentially inhibit its growth, so why don’t we just turn this into a breast cancer drug?” Walpole agreed to do that but we backed off the idea because it wasn’t going to earn enough money! So Walpole proposed the following, “How about this: if we put the drug on the market and stop selling it, but then you find a clinical use for it”. Everything after that was working on how to use tamoxifen. From that sprang long-term adjuvant tamoxifen therapy and chemoprevention. All of that is the standard of care and FDA approved right now.

  1. Just before ASCO 2018 you were elected as one of the giants in cancer care, many congratulations from us for that honor. Can you tell us a little bit more about this and what it means to you?

V. Craig Jordan: It was rather a pleasant surprise, because I am only 5 foot 11! I didn’t realize that I was now elevated to be a giant! It was a wonderful surprise. As it turned out, I didn’t know that Dr. Abderrahman, my Fellow at the moment, was now sneaking behind my back and getting me nominated in conjunction with one of my former mentees Dr. Ruth O’Regan, who is now the Chairman of Hematology-Oncology at the University of Wisconsin-Madison. My Tamoxifen Team all turned up to cheer me on. It was really quite emotional to have them around. It was humbling and surreal, because you spend a lifetime simply doing what you love and not necessarily realizing the impact of what you do, but then when they said, ‘You have changed medicine, everything changed with what you have done with transitioning from the era chemotherapy to the era of targeted therapy,’ it suddenly hits you and so I am very grateful, and glad that there are millions of women, and I emphasize this, millions and millions of women who have benefited from both tamoxifen and SERMs and still do.

  1. Balkees Abderrahman, how was V. Craig Jordan’s mentorship and how has it made a difference to you and your career in cancer research?

Balkees Abderrahman: Well, this is actually a very crucial and dear topic to me because altruistic mentorship is, in fact, career changing and character defining altogether. I am just one among many individuals in the Tamoxifen Teams whose life has been changed because of Professor Jordan’s personal decision or choice if you like to take interest and invest in the young. But that’s not all, a mentor’s greatest talent is to see potential growth and hidden areas of talent in mentees who are not accomplished yet, and even when the mentees might not see this in their own selves. The mentor’s greatest skill is then to help unleash that potential.

That very talent and skill is Professor Jordan’s Finest Hour in my opinion. So, when I joined his research team I was very enthusiastic, I had the energy, and was willing to work hard, but he saw my hidden potential, and chose to utilize his time and skills, to shape me from that rough rock to becoming more of a diamond, facilitating my ascent as an accomplished professional women. The fact is no one starts accomplished or is born ready, nonetheless, many can still be considered talented at these early stages. His practice of mentorship has also helped grow my character not only my scientific career, and that aspect is often unspoken of but is very much priceless. He is a very humane mentor; kind, understanding and generous and this live example or role model has persuaded me to follow suit.

Despite all the academic obligations and even the health challenges, he is always there for his mentees and colleagues. He has been taking care of them for over 30 years now, making sure that their careers are advancing and that they are going well. This inspired me to mentor the young people myself. I decided that despite being overwhelmed with many commitments, I have to pay it forward because my career would not be where it is today but for him so I ought to do the same to someone else. This would not have happened if I did not see this example in front of me, and this could not adhere any better to one of my favorite NYT columnists, David Brooks, who talked about personalism as the philosophy of life that we desperately need today. “The reason for life, Jacques Maritain wrote, is “self-mastery for the purpose of self-giving.” It’s to give yourself as a gift to people and causes you love and to receive such gifts for others. It is through this love that each person brings unity to his or her fragmented personality. Through this love, people touch the full personhood in others and purify the full personhood in themselves.” He said. The truth is, education does not consist merely of acquiring few facts in science and medicine or literature, it is about the development of character.

What is really remarkable is this article that I read just today, shared by one of my favorite authors and thinkers, Adam Grant, with the title “The Bell Curve is about policy. And it’s wrong”. I thought, “Hmm, this heading is worth reading” The article basically highlights the sustainable value of teaching and mentorship. It says that if a classroom of 28 had a better teacher for a year, their lifetime income would increase by: Over $260k if a bottom 5% teacher is replaced with an average one, and over $560k if an average teacher is replaced with a great one. This socioeconomic impact is quite frankly staggering. This is why universities and all educational institutions must invest in the young and focus on recruiting, retaining and rewarding fine mentors, because the lack of investment is directly associated with sacrificing their futures.

V. Craig Jordan: I wish to add to Dr. Abderrahman’s comment. The thing that I saw in her despite her young age or relative lack of experience, was the fact that she actually has this imagination in science and she can write like composing a Sonata. I have had some brilliant people over the past years, vice presidents of pharmaceutical companies, chairs of departments, just outstanding people, of whom I can compare Abderrahman to, and she is outstanding. She can weave intellectual debates and put them down on a piece of paper. Those thoughts gripped the editors of Nature and Science magazines – something I never did myself! Despite having me at bay, she works on her own with the editor to make it happen, I am not involved. She is a self-starter.

  1. Balkees Abderrahman, do you have anything further to say on that?

Balkees Abderrahman: As I had emphasized earlier, it is crucial. What I wish to add is that we need to really focus on mentorship as a requisite component to every academic and educational environment. I look at all the amazing people in science and medicine, all of whom whether they like to admit it or not, have been helped at one point or another by other people to be where they are. One’s life is rarely the making of his/her own, it is instead the dynamic integration of one’s doing, others’ doings, and ongoing random or planned events. We all possess the “giving back” capacity, and although it varies in nature, shape, form, and impact, it exists across at all stages of one’s career. Creating a sense of community and family is essential in mentorship and that’s what Professor Jordan established. Academia is quite tough and there is a lot of stress. That being said, emotional support really goes a long way! There is a recent study in Nature, which concluded that a lot of undergraduate students and even physicians (I believe it’s not just at the undergraduate level), suffer from acquired depression and mental illness. One of the culprits identified in that article is the profound lack of mentorship. Mentor is a loaded word, a mentor can be a role model, a shoulder to rely on, a friend, and this is why the word ‘mentor’ holds a different weight in the dictionary compared to the word ‘supervisor’.

  1. V. Craig Jordan what is next for you in terms of projects or research?

V. Craig Jordan: Very good question. Three things, number one: consolidate my tamoxifen team. When I was at the University of Leeds I created an infrastructure enriched with young undergraduates and we ended up with 30 medicine-changing publications– this was unheard of! I went to Bern, Switzerland, built the Ludwig Institute for Cancer Research in one year, with an infrastructure of clinical investigators from all around the world and they became my friendship group till this day. Although I was a scientist, I was orchestrating a group of clinicians, who are able to receive the fundamental translational research carried out by scientists and then translate it into lives saved in the clinics. I went to the University of Wisconsin, where my tamoxifen team was about 10 PhD students, a few postdocs and some technicians and we made SERMs that revolutionized women’s health. This formulae, the few capable and committed of the young, works wonders. Everybody was keen and enthusiastic. The university working environment was exceptional! The sky wasn’t the limit. We started working on clinical studies and we easily went to the freezers and got our patient materials – it was all there within an arm’s-length, absolutely essential to get things done efficiently. It has got far more complicated now, you can’t do this and you can’t do that. There are so many laws saying this patient material is secret, etc and that in a way hinders the smooth trajectory of innovation. It is all a completely different world now– there is such a huge amount of paper work and branched administration to be able to get any interaction going, even in one’s own institution.

  1. Balkees Abderrahman can you tell us a little bit about one of the projects that you are working on currently.

Balkees Abderrahman: Actually I am very excited about one project in particular. Dr. Jordan and I are working hand-in-hand on a novel project in our laboratory. I fell in love with the unfolded protein response machinery, this sophisticated yet simple machine that dictates the decision-making of life or death in many cells and is involved in fetal development, nuerodegenerative diseases (i.e. Alzheimer, Parkinson, etc), inflammatory diseases, immunity, and cancer. There are so many exciting, nonetheless, moving parts to this story that we are trying to decode; shed the light on it’s poorly-understood molecular underpinnings and what constitutes the switch in such decision-making. We either exclusively developed or acquired unique models such as breast and prostate cancer models that paradoxically undergo apoptosis with oestrogen and testosterone, subsequently. These cancer models share a biological signature with other non-cancer models such as cytotrophoblasts which are cells in the placenta, osteoclasts which are considered the bone resorbing cells and are responsible for osteoporosis in postmenopausal women, and thymocytes which are immune cells, all of which undergo apoptosis with oestrogen as well.  These are completely different models and yet they share a stress or death signature. We are hoping that our novel laboratory work will contribute to better understanding this fundamental piece of biology and propose therapeutic targets for future cancer therapy.

V. Craig Jordan: To add to that, one of the visions that I basically had was to conclude with this unique biology based on everything that we have done in the last 40 years – we have targeted the oestrogen receptor with anti-oestrogens, we have done long-term adjuvant tamoxifen therapy, and we understood drug resistance to tamoxifen. This biology happens to be in cell models that become vulnerable to die with oestrogen after developing tamoxifen resistance with long-term adjuvant tamoxifen therapy. It all started with Doug Wolf’s serendipitous finding, once my PhD student, now Senior Director at Pfizer Pharmaceuticals (NJ, USA). Doug seemingly made a catastrophic discovery. One of my earlier PhD students Marco Gottardis, now Vice President of Prostate R&D in Janssen Pharmaceuticals (Belgium), studied tamoxifen resistance in animal models as we couldn’t do so in vitro. But then Doug came along and I asked him to study growth factors in Marco’s models and I wanted him to grow up the tumours with tamoxifen, then split them into 3 groups: placebo, with tamoxifen still, and with low-dose oestrogen. This is what we see clinically with metastatic disease. We didn’t see Doug for about 6 months. I mean he would hide in the toilets if he would see me coming – he was sort of terrified. He said we are going to have to withdraw all Marco’s papers because he was unable to replicate his results. This was like a hammer blow.

I said, ‘Tell me what you found’, and he said that he had done it three times and checked everything. He added: “we take the tumours and grow them up with tamoxifen just as you said. But when the tamoxifen capsules were taken out and a capsule of oestrogen was put afterwards in the low-dose oestrogen group, all the tumours had disappeared!! They died, not grew with oestrogen, opposite to what Marco had shown in this model” When I asked for how long we had been doing this, Doug said, “5 years”. It turns out that Marco had shown one phase of the resistance but Doug found a new phase that follows over time. I remembered a piece of history. Sir. Alexander Haddow, used high-dose oestrogen therapy to treat metastatic breast cancer in postmenopausal women. He had a 30% response rate. Women can be oestrogen-deprived either naturally as in what happens with menopause or with tamoxifen treatment. Five years after menopause or 5 years of oestrogen withdrawal with tamoxifen blocking the oestrogen binding to the oestrogen receptor in these cells, you end up with a new population of breast cancer cells through selection pressure. Now if you put high or low-dose oestrogen, the tumours just melt away. I looked at all of Doug’s graphs, the tumours just melted away, disappeared. I said, “Well then, we have discovered something brand-new, we have discovered what happened with Haddow’s patients, and this is clinically relevant. So we will study it, and now we call it oestrogen-induced apoptosis”. So, now Dr. Abderrahman’s mission is to decipher this unique discovery and uncover the molecular underpinnings. We have got a comprehensive model system that we can use to do so. Therefore, why can’t we try and find out how we unleash that machine of death in cancer cells and attain a response rate higher than 30% (as seen in breast cancer) and higher than 55% (as seen in prostate cancer). This will help to find a way to supplement the current therapies; not just hold cancer with long-term anti-hormone therapy but kill them as well.

  1. A final question for both of you – how do you see the era of cancer research changing over the next few years?

V. Craig Jordan: I’d like to give the global view. What we have now is a massive expansion within the pharmaceutical industry. Instead of focusing on five or six promising compounds as it was 30 years ago, now were are trying to find a therapeutic use for tens and tens of hundreds of drugs out there. What concerns me the most is that we are going to get further and further away from the basic principles of therapeutics and therefore patient benefit. Yes, we have so many drugs, but how are we going to get the drug to the site with least toxic effects? Are there any established prognostic or predictive tests to predict its efficacy? What is happening is that drugs are being tested in individuals skipping all of that.

Also, we have got to get away from the last stages of cancer and focus more on the earlier stages of cancer where cure is more attainable. And what about prevention? As one contemporary example, immunotherapy is going to be a hard sell to early stages because there are so many side effects and we don’t have a marker to say who will respond and who won’t. So, millions of dollars are going to be spent, and we don’t know if a notable portion of the population will even get a response. Say you have a relatively healthy person who has very little metastatic spread, generally fit and well, and you decide to give him/her a drug that is toxic. Suddenly they are getting some life-threatening side effects on the off chance that they are going to be cured or live for extra few months – that has got to somehow change. We have to break the curse of what has been done with chemotherapy: no test, just give the drugs.

Balkees Abderrahman: What I really hope for cancer care is that we move from the concept of “precision medicine” to what I would like to see as “sustainable medicine”.  Of course, it is rather great to have advanced and targeted therapies, but if this therapy is toxic or if it affects the quality of life for the patients, and it cannot be given to everyone because it is so expensive, then have we really advanced cancer care as one would claim? This is “the million dollar question”. We have this amazing human intellect and all this remarkable effort and immense funding, but we cannot make a drug available to everyone or we cannot make a patient’s life worth living when given a certain treatment. So, this is a very important area that I hope we will actually advance in. The other thing is that the current design of randomized clinical trials falls short and those clinical trials are actually the ones literally dictating our health care systems. It’s like the blind leading the blind. Nobel Laureate, Sir Angus Deaton (Princeton University, NJ, USA), is a British economist, who won his 2015 Nobel Prize for his brilliant analysis on welfare, poverty and consumption. Deaton alongside his colleague Nancy Cartwright (University of Southern California, CA, USA; Durham University, UK) said that a notable portion of the results of health economics from randomized clinical trials is actually unreliable. How daunting?

We have to pause and seriously think about this and how we can fix such faulty system. The endpoints of a lot of clinical trials are not necessarily associated with clinical survival benefits and this inevitably lowers the benchmark for patient clinical benefit. Needless to say, right now we have a lot of fashion and fads out there. As physicians, scientists and physician-scientists, we’re and always should be evidence-based. We want to make sure that we will not misguide our patients or the funding. Therefore, our priority for the future is to fix these current flaws and hopefully progress into greater things.

 

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