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Targeting Pancreatic Cancer with Radiation & Immunotherapy During the Branches

As a student at the University of Michigan Medical School, your last two years of school are collectively referred to as the Branches. Essentially, it’s a flexible framework of elective time that allows you to pursue your unique interests. Although the prospect of customizing two years of scheduling might sound daunting to some medical students, don’t worry, each student receives individualized support and mentorship through a Branch advisor. Due to my interest in radiation oncology, I joined the Diagnostics and Therapeutics Branch, and for advising I was paired with Dr. Michelle Kim from the Department of Radiation Oncology.

As someone who is passionate about translational research, I wanted to pursue my research interests in pancreatic cancer. More specifically, I wanted to build off the work I started in the summer after my M1 year. I worked in the Morgan radiation oncology lab assessing novel molecularly targeted agents as tumor cell-selective radiosensitizers for pancreatic cancer. One drug in particular, a DNA-PK inhibitor, demonstrated profound radiosensitization, and even more intriguing were preliminary findings that it might substantially stimulate the immune system.

Subsequently, during my M2 year of core clerkships, I saw firsthand how major breakthroughs in immunotherapies for several solid tumors, such as melanoma and non-small cell lung cancer, were rapidly changing the landscape of oncology. And I wanted to apply some of the concepts behind these immunotherapeutic strategies to pancreatic cancer in the context of targeting the DNA damage response.

Since the core principle underlying radiation’s immunogenicity is DNA damage and creating genomic instability, I thought we could potentiate the immunogenicity of radiation for pancreatic cancer by employing a DNA-PK inhibitor that would inhibit the most common mechanism for DNA double-strand break repair (i.e., non-homologous end joining). I hypothesized that this would increase both the rate of immunogenic tumor cell death and the absolute quantity of unrepaired cytosolic DNA, both of which would initiate an immune response.

One important caveat to this robust immune response is that cytotoxic T cells – important for killing cancer cells – have checkpoint proteins that can turn them off if they are active for too long. And this is why I hypothesized that immune checkpoints inhibitors – anti-PD-L1/PD-1 drugs in this scenario – play a critical role in maintaining a strong, sustained anti-tumoral immune response following treatment with radiation and a DNA-PK inhibitor.

My proposed therapeutic combination of radiation, DNA-PK inhibitor, and immune checkpoint inhibitor has generated compelling pre-clinical data thus far, but there is still plenty of work left to do before translation from bench to bedside. Fortunately, I have a supportive mentor, Dr. Meredith Morgan, and numerous collaborators in the lab (Sarah Zhao, Qiang Zhang, Josh Parsels, and Leslie Parsels) who will help with the project while I am completing clinical electives.

My Branches story might sound like a niche experience, but there are countless other opportunities for you to pursue your unique research interests within Michigan Medicine. Your Branches experience is not meant to conform to a one-size-fits-all construct; rather, your schedule is customized to align with your individual interests. Before you start your Branch years, you meet one-on-one with a Branch advisor to define your area of interest and create an individualized development plan. And, during the Branch years, you meet with your Branch advisor on a monthly basis to discuss your progress and goals.

Other valuable resources available to Michigan Medical School students include the Paths of Excellence. Since I am interested in research, I joined the Scientific Discovery Path. Through this Path, you learn about the different types of research available to students at the Medical School and they can facilitate research opportunities tailored to the student’s individual interests. This Path can also assist with applying for research grants, including a select number of NIH grants available to University of Michigan medical students on an annual basis. There are also numerous grants offered through the medical school to fund students’ Capstone for Impact projects.

I am also currently the co-president of the Radiation Oncology Interest Group. Since radiation oncology is a small field with limited exposure built into the core curriculum, we aim to bridge this knowledge gap through organized dinners where students can interact with faculty and residents to learn more about the specialty. In addition, we facilitate shadowing and research opportunities within the radiation oncology department for medical students.

I hope the story of my Branches experience will spark the interest of prospective students who are interested in the research opportunities available to medical students at the University of Michigan Medical School. And, if you are interested in working with radiation therapy, DNA damage response inhibitors, and immunotherapy for solid tumors, the Morgan lab at the University of Michigan Medical School would be an excellent place for you to pursue your interests.