Lessons Learned, with Pier Paolo Pandolfi

Don’t be afraid to make a U-turn toward your true calling

My first major was actually philosophy. In Europe, you have to choose either medicine or philosophy, so I chose the latter. My family were all in humanities. I really loved philosophy – and still do – but, during my studies, I realized the topics that stuck out to me were based in the core of scientific reasoning: epistemology, philosophy of science, logic, you name it. So, I asked myself: Do I just want to discuss science, or do I want to become a scientist?

Because of my late switch to medicine, I was quite old when I finally graduated. Luckily, the speed at which my early career was propelled made up for it. During my final year of study in medicine, we ended up cloning the translocation associated with acute promyelocytic leukemia (APL). That discovery was transformative for me, the research group, and patients – but it was just the first step; in the following years, we were able to model the disease in mice. It’s because of this work that I was later recruited by Memorial Sloan Kettering Cancer Center in New York to run my own lab. While there, my colleagues and I completed the bench-to-bedside cycle by testing drug combinations that might cure APL. A derivative of vitamin A (ATRA) plus arsenic trioxide, or ATRA plus histone deacetylase inhibitors, proved effective and curative.

That early stretch of my career was during the Clinton era in the USA, when the National Institutes of Health (NIH) was extremely well-off, so it was a fantastic start for me. In subsequent decades, the economy has slowed down, but despite that and the restrictions and issues with this administration, I think the US remains a beautiful place for research (especially Boston!). It really is an exciting environment, full of brainpower, inspiration, and research.

The “eureka” moment can happen at any time – even after discovering limitations

The story of APL was a fantastic journey (1). Much more recently, we discovered that behind the metastatic process in prostate cancer is what we call a “lipogenic switch” – and we believe this could generalize to other forms of cancer as well. In other words, we realized that cells prone to metastasis activate a lipid-building program, orchestrated via a SREBP transcription factor. This discovery was interesting in its own right because it was triggered by the loss of a gene called PML, which I had studied for a long time because it is involved in the pathogenesis of APL. We found that PML is also lost in 20 percent of metastatic prostate cancers.

This led to another “eureka” moment. We realized that the field might have made a fatal error in modeling metastasis in mice – simply by not taking into account an easily-missed consideration. The error was in their feed; the mice were fed the standard, relatively low-fat chow that had been the norm for mouse models for the past 20 years. When we switched the mice to a high-fat diet (combined with inhibitor drugs), lo and behold, we saw evolution into aggressive or metastatic cancers. The new model showed genetic, molecular, and environmental support for the notion that fat – either endogenous or exogenous – is a very important ingredient to fuel metastatic spread.

The first author of the study and I are discussing going deeper into our findings on all fronts, to better understand whether or not there may be a lipogenic signature in other diseases, such as prostate cancer. We’re collaborating with a group that has collected prostate cancer samples from obese people in an effort to test which fats might provoke a negative effect. We’re attempting clinical trials and discussing which of the SREBP inhibitory pathways are clinically viable. We have also talked about the idea of diet – can we do trials with diets? Can we put advanced prostate cancer patients on low-fat diets? But that’s a conversation for another day.

To excel, you may need to make a tough call – there are only so many hours in a day…

In the early stages of my research, the idea that one would have genes that caused cancer was beginning to emerge, and that fascinated me. Since then, I’ve never doubted that I wanted to focus on oncology and molecular biology. As a student, the more lab work I did, the more excited I became by it, to the point where – relatively early on – I knew that I wouldn’t be a practicing physician even though I am board-certified. Because of my APL work, I’ve been lucky enough to pursue my research aspirations and direct a scientific team since the beginning of my career.

Those who love lab work and want to see patients face a challenge; it’s not easy to be cutting-edge on two fronts. Because each essentially requires 24/7 work, you’d have to clone yourself to excel in both! This is not to say that it’s impossible, because I’ve known a number of people here at Harvard Medical School who have managed that difficult, but rewarding, path. My advice to those early in their career is to focus on either the research-based or the patient-facing aspect of medicine. However, as the field moves forward, especially in pathology, those two aspects are coming closer together – so maybe that decision won’t need to be made in the future.

Enjoy rewards wherever you may find them – but remember that you rarely work alone

From my perspective, the many honors I’ve received have not been for me alone; they’re always for my entire team, who all work tirelessly. I may be the “coach” but, in the end, it’s the team that wins the game.
Work in this field is extremely demanding, so honors, in my mind, are a motivation to keep you going. I’m especially grateful to have been honored by my home country of Italy, where I received a knighthood in 2015. Even though I don’t live there anymore, it’s good to be recognized for my work, because people are sometimes rejected for leaving their home country to pursue work elsewhere. I’ve been fortunate to have tremendously positive relationships with my collaborators in Italy and often help with research there. I could have stayed in Italy, or even London, but opportunity called for me in the US, and I think any scientist should prioritize that over a sense of obligation to their home, especially early in their career.

There are very few things as rewarding as being recognized for something that not only does good for humankind, but also makes you proud and happy. Discovery, in its own right, is very rewarding – so the idea of understanding something better makes me extremely fulfilled, and the fact that it’s a paid career is just a bonus!

The real lesson, and my eternal motivation, is to set the bar very high. We’re in this game to cure cancer so we will have to fight hard with every bit of strength if we want to bring that goal to fruition. It’s a tough battle, but one worth fighting.