Postdoc Feature Series with Salvador Alonso Martinez

Our latest installment in the Postdoc Features series promoting the research and lives of our impressive postdocs and postdoc alumni. 

For future features, we are actively looking for interested postdocs! Please use this form to sign-up or to suggest the name of a colleague that you would like to see featured. Features will take the form of informal interviews or brief video abstracts of recent research (featuree's choice!). We hope this will be a great chance to (first and foremost) draw attention to the fantastic work and researchers in our postdoc community, while also providing the opportunity to develop research communication skills and share advice about the postdoc experience.

 We look forward to featuring you!

 Sincerely,

Heidi Meyer & your Postdoc Association.

Salvador Alonso Martinez

Visiting Fellow and Postdoctoral Associate with Dr. Luke Dow in the Department of Medicine.

Recent Achievements:

ASCO Young Investigator Award 2021 MSKCC T32 Clinical Scholars

Recent Publications:

• Alonso S, Dow, LE. Engineering and Studying Chromosome Rearrangements in Cancer. Dis Model Mech. (Forthcoming).
• Alonso S, Saltz L. The Landmark Series: Chemotherapy for Non-Metastatic Colon Cancer. Ann Surg Oncol. 2021 Feb;28(2):995-1001.
• Alonso S, Yilmaz ÖH. Nutritional Regulation of Intestinal Stem Cells. Annu Rev Nutr. 2018 Aug 21;38:273-301.
• Alonso S, Jones RJ, Ghiaur G. Retinoic acid, CYP26, and drug resistance in the stem cell niche. Exp Hematol. 2017 Oct;54:17-25.
• Alonso S, Hernandez D, Chang YT, et al. Hedgehog and retinoid signaling alters multiple myeloma microenvironment and generates bortezomib resistance. J Clin Invest. 2016 Dec 1;126(12):4460-4468.

What background led to your current position?

I grew up in Mexico and also went to medical school in Mexico. After finishing med school, I moved to Baltimore for a postdoc at Johns Hopkins, where I did research in leukemia and myeloma. In 2016 I was accepted at MGH (Massachusetts General Hospital) in Boston for an internal medicine residency program. In 2019 I started my oncology fellowship at MSK. Currently, I am a second- year fellow with my clinical affiliation at MSK and I also carry out research as a postdoc at Weill Cornell. I am a physician scientist, so that means I am an MD who dedicates a significant portion of my time to research, while also dedicating time (10-20%) to direct patient care. I see patients on Tuesday mornings, while the rest of the week I am in the lab doing basic research. Oncology fellowship is four years in total, including three years of research. Traditionally, the first year of fellowship is 100% clinical, meaning your only role is patient care. Then the second and third year are research, either clinical or basic. If you choose basic research, you will quite often take four years, as in my case, to finish your projects.

What made you decide to pursue training as a physician scientist?

During med school I spent a summer in Houston doing research. For 10 weeks I was in the lab and I really enjoyed understanding cancer biology and genetics. Then when I went to Hopkins for my postdoc, I became even more interested in cancer research. Overall, trying to understand cancer from a more foundational perspective was very interesting to me.

What is the basis of your current research project?

My focus in both the lab and the clinic is colorectal cancer (CRC). In the clinic, about 80% of the patients I see have colon or rectal cancer. In the lab, my current project is focused on understanding therapy resistance in CRC. We are using different technologies like lineage tracing, shRNA, and CRISPR screening, to understand how CRC cells become resistant to different therapies. My main focus right now is on WNT-inhibition. Ultimately my goal is to expand this focus and understand mechanisms of resistance to other targeted therapies. The main model system that I use to carry out this research is organoid cultures. These are 3D lines that are grown in a synthetic extracellular matrix called Matrigel, and they provide a better representation of human cancer than traditional cell lines. For readout, the tools we use regularly are next-generation sequencing, flow cytometry, and qPCR. Although I am focusing on CRC, the hope is that our findings may be relevant to other cancer types.

My lab project takes over 80% of my time, but I also try to be involved in more translational or clinical projects. This work involves analyzing patient databases and looking for how patients respond to chemotherapy, what specific mutations are associated with response to treatment, etc. I think it’s important during training to be involved in different types of research, not only to get more expertise, but also to get a sense of what you like the most.

How does your work relate to the clinical trial process?

For clinical trials, usually the first step is to home in on something that is promising in basic research and translate it into a phase I trial. A phase I trial is usually a small study, anywhere between 10 to 50 patients, and the goal is to make sure that whatever you are testing is safe. Efficacy is evaluated in phase II and especially in phase III trials, but for phase I it’s all about safety. Phase I trials start by giving small doses of a new medication, and if patients tolerate it, the dose will be increased gradually until side effects start to emerge. A phase II trial is slightly larger than a phase I, maybe 20 to 100 patients, and you continue checking for safety but also start to evaluate efficacy. Then in a phase III study, efficacy is really the emphasis. Overall, once you prove that the medication you are giving is safe, you can move on to efficacy in a larger population. One of the reasons why I chose to pursue basic research instead of clinical research during my fellowship, besides my interest in cancer biology, is because it's easier to transition from lab-based research to clinical trials than the other way. I would eventually like to be involved in clinical trials, but for now my focus is in the lab.

What are some of the challenges associated with research aiming for clinical trials?

One of the biggest challenges is probably the very high attrition rate of new treatments. Many new treatments or new therapies that have activity in mice or in cell lines, don’t have any benefit when they are translated to patients. For example, in cancer only 5% of all therapies that are tested in clinical trials eventually receive FDA approval. This means that 95% of all therapies that are discovered in the lab fail to be approved and are never used. As a consequence, doing research is pretty expensive when you only have 5% of new therapies being approved.

One of the reasons for this high attrition rate is that many of the systems we use in the lab don’t accurately model human cancer. In our lab and other groups, we are trying to generate new systems that better recapitulate human disease. For example, we use organoids instead of 2D cell lines, because we know that organoids better model human cancer. In addition, we are increasingly using gene editing technologies that more faithfully model oncogenic mutations observed in patients, compared to the traditional transgenic or knockout approaches. We hope that by using tools that better recapitulate human disease, the attrition rate of new treatments is going to improve.

What are your plans for the future?

I have two more years of oncology fellowship. I will continue expanding on my current research projects, and eventually prepare an application for faculty positions. In the future, I’d like to lead a translational lab with a mix of clinicians and PhDs. There are so many techniques and perspectives that you need to have in the lab to carry out really effective research, so I would want to emphasize different backgrounds.

What resources at MSK and WCM have you found to be most helpful for your training?

I think we have many, many resources through MSK and Cornell. At MSK we have a large sequencing project called “MSK-IMPACT”, where we analyze patient’s tumors for the presence of ~500 cancer-associated mutations. To date, about 70,000 tumors have been sequenced. With this resource we can analyze, for instance, what mutations correlate with patient survival or response to specific therapies. At Cornell and MSK we have patient-derived tissue banks, which we can use for sequencing or to test the effect of different therapies.

What is the best part of being a fellow/postdoc?

For me, for sure, it’s autonomy. Especially after being through residency and then fellowship where we often are supervised by more senior physicians, and we have a more fixed schedule. In the lab the schedule is more flexible, and I have the autonomy to decide what I want to work on in a given day - I really value that a lot. 

What do you wish you would have known before pursing training as a physician scientist? For the most part, I think I knew what I was getting into. I think in clinical research and patient care, we are used to getting data and seeing results early (days to weeks). In the lab, I often have to remind myself that experiments and results take longer. It’s very important to be patient and take one step at a time.

What advice would you give to those interested in becoming a physician scientist?

Going back to the last question, my advice would be to take one step at a time, and to ask for help when something doesn’t make sense. People are always willing to help.

What’s your favorite thing about living in NYC?

I like that you can do almost any activity, and find any type of restaurant or store within 10-20