1. Neff Newitt, Valerie

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Sidharth V. Puram, MD, PhD, expected to become a patent lawyer when he began his undergraduate studies at the Massachusetts Institute of Technology. Little did he realize he would eventually become a clinician, Assistant Professor of Otolaryngology-Head and Neck Surgery at Washington University in St. Louis, and an emerging researcher exploring tumor heterogeneity.

Sidharth V. Puram, M... - Click to enlarge in new windowSidharth V. Puram, MD, PhD. In his spare time, Sidharth V. Puram, MD, PhD, takes to the stage performing as a dancer. "I love to dance and performed with Indian dance troupes that were mostly part of Indian culture shows."

Now a husband and father to two young children, this native of the Twin Cities in Minneapolis, Puram said his research interests "... revolve around using advanced genomic technologies to better understand the nuances of intra-tumoral heterogeneity in head and neck cancer."

Sidharth V. Puram, M... - Click to enlarge in new windowSidharth V. Puram, MD, PhD. Sidharth V. Puram, MD, PhD, works at Washington University in St. Louis using "advanced genomic technologies to better understand the nuances of intra-tumoral heterogeneity in head and neck cancer."

It's quite a professional and scientific leap for the former high school student who once excelled on the debate stage and imagined going into law.


"I was very committed to competitive policy debate and, fortunately, was successful in doing that. But of course, as a high school student, you don't really get much exposure to the contributions one can make within biology," Puram recalled.


Once at MIT, however, Puram began to realize how much more consequential a career in medicine and science might be.


"I was highly encouraged to do research there, so I applied for a position in Dr. Bob Langer's lab that looked at a delivery of DNA vaccines for stubborn diseases like HIV, Hepatitis C, and other disorders," he said. "It was focused on the chemical engineering side of things-how to actually get vaccines delivered into cells in order to trigger an immune response. We used degradable polymer microspheres to accomplish this goal, and I found a lot of love for this process of discovery.


"I ended up being in that lab for nearly my entire 4 years at MIT and, by the end, I knew I wanted to pursue some component of research alongside medicine. I still felt strongly about trying to help people directly through clinical care, but through that lab experience, I realized research can have a major impact on a larger swath of people."


Puram admits that it wasn't all science and research during his college days. He found his way back to the stage, but not as a debater. Rather, he performed as a dancer. "I love to dance and performed with Indian dance troupes that were mostly part of Indian culture shows." Even today, Puram enjoys organizing and participating in dances for weddings and other events.


Laboratory Work Ensues

After graduating from MIT, Puram went to Harvard Medical School where he received both his MD and PhD in a combined Medical Scientist Training Program. He completed residency in the Harvard Combined Program of Otolaryngology-Head and Neck Surgery, primarily centered at Massachusetts Eye and Ear Infirmary, followed by fellowship training in head and neck surgical oncology and microvascular free flap reconstruction at Ohio State University's James Cancer Hospital.


Puram assumed his current position in 2019, "... excited about the possibility of contributing to medicine, beyond individual patients who might come in or out of my clinic, which is certainly rewarding in itself."


His contributions are directed toward better understanding head and neck cancer, specifically the nuances of intra-tumoral heterogeneity.


"We are interested in understanding how the tumor ecosystem might contribute to very challenging problems that persist in cancer, such as tumor persistence and tumor recurrence," Puram noted. "We don't know why certain tumors seem to fail after treatment, while others do not. Lastly, we want to discover which tumors are at risk for metastasis and which are not. These are problems that have plagued the oncologic community for years, and we still don't have great explanations for most of them. That is what makes this such an exciting area of research."


While metastases and recurrences are challenges throughout the field of oncology, "in head and neck cancer, we know that once a patient has a neck metastasis, survival drops immediately by half," said Puram. "Understanding why certain tumors metastasize, or how to treat those tumors better, would offer a ton of opportunity for growth and improvement in oncology."


Puram feels fortunate to have a 10-member team-comprised of graduate students, post-docs, and staff scientists-in his laboratory. "On a day-to-day basis, we are culturing cells in vitro, as well as using in vivo animal models to grow patient-derived xenografts, with integration of such models using cutting-edge technologies," detailed Puram.


His team leverages various sequencing approaches such as single-cell RNA sequencing or spatial transcriptomics to better study the diversity of cell states that exist and the nature of how the cell states are really driving the biology.


"For example, if we think a population might be to blame for a certain phenotype, we might try to grow out those cells and culture them, and then compare how those cells resisted treatment or more readily spread/metastasized, for example, compared to the other cells within the tumor," said Puram.


What Findings May Reveal

Currently completing single-cell sequencing studies of a variety of different head/neck subsites, Puram said, "We are trying to better understand how heterogeneity among HPV-positive tumors might influence the more favorable prognosis. We are also completing studies to better understand a partial epithelial-to-mesenchymal transition (EMT) program that we've described previously (Cell 2017; doi: 10.1016/j.cell.2017.10.044). Now we are trying to better identify and understand the external signals that drive this partial EMT state and its downstream targets. How is it affecting changes in the cell and making cells more aggressive?


"We know these partial EMT cells, which we previously showed are at the edge of tumors, seem to correlate with negative patient outcomes," Puram noted. "And we're starting to unlock some of the regulators, which appear to be members of the TGF-beta family, as well as some of the downstream effectors which include some of the EMT transcription factors, though not all."


Asked what a greater understanding of those EMT cells might ultimately mean, Puram replied, "Two things. One, we hope to be able to use those cells and their presence as a marker of tumors that may need more aggressive treatment. Similarly, tumors that don't have those cells may need less-aggressive treatment. We can prevent ourselves from overtreating patients, and avoid radiation in patients with more favorable tumors, for example. The second thing is if we can develop drugs that specifically target those cells, then we might be able to improve on the outcome of those patients in a more biologically directed and targeted manner."


Clarifying both the short- and long-range goals for his lab, Puram said, "In the short run, it's trying to understand the biology that underlies these specific cell populations and their contributions to different cancer phenotypes. In the long run, it's trying to figure out how we can use such cell types as a prognosticator, developing a 'tool' so clinicians can test patient samples to predict who has 'bad disease' versus 'favorable disease,' and targeting these programs to provide more directed therapy.


"Right now, when you take a tumor and you sequence it, you don't know which genes are actually relevant. It might be that there are genes that are going up (i.e., overexpressed) that are actually arising from immune cells and actually relevant for improving the outcome of the cancer. But we don't know whether those genes that are up or down are good or bad, because we simply don't know where they are coming from. That represents a fundamental problem. We need to understand the whole system."


In terms of patient outcomes, Puram hopes that his work will eventually allow clinicians to stratify patients into those who need more treatment or less treatment, and "provide opportunities to target specific aspects of a patient's cancer life cycle."


"Maybe we can provide a drug that, even when a patient is totally cancer-free, can help stop the cancer from coming back by targeting a program related to recurrence," he stated. "Or maybe we can give a certain drug to a patient who is at high risk for metastasis or a certain drug to a patient who already has metastasis, because we know what those metastatic cells look like. The implications of our research and the potential impact on patients are very far-reaching."


Puram hopes others in medicine will truly digest the fact that cancer cells are not all the same, and there is significant heterogeneity.


"This heterogeneity is very important," he stressed. "The revolution in our knowledge regarding these cells is going to be instrumental in providing a deeper, more nuanced understanding that is likely to significantly change the way we view oncology and understand cancers more fundamentally. The idea of moving from grinding up a tumor and looking at it as a homogeneous ball of cells with genes that are expressed to actually understanding what each of those cells are doing, what their individual role is, and what their significance is, comprises a new perspective in the way that we think about cancer."


Valerie Neff Newitt is a contributing writer.


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