Remembering Dr. Supriya “Shoop” Saha

Short abstract

The cholangiocarcinoma community has truly lost a young, talented, bright star, Dr. Supriya Kumar “Shoop” Saha. Despite his passing, he continues to inspire the search for a cure.

Dr. Supriya Kumar “Shoop” Saha passed away on May 6, 2020, after battling complications from a bone marrow transplant for the treatment of myelofibrosis. He was only 40 years old. A prolific young physician scientist and a rising star in the field of cholangiocarcinoma research, he had accomplished so much in his short career. His untimely passing left an enormous sense of emptiness to those who knew him.

We had the pleasure and good fortune to work with Shoop closely when he was a Medical Oncology Fellow and a junior faculty member at Massachusetts General Hospital (MGH), Harvard Medical School. Shoop was born in Louisiana spent the later part of his childhood in California and South Carolina. After graduating from Harvard University, magna cum laude, in microbiology and biochemistry, he joined the Medical Scientist Training Program at University of California, Los Angeles, as a Terasaki Fellow and obtained his M.D. and Ph.D. there, with a research focus on molecular immunology. Working in the laboratory of Genhong Cheng, he made significant breakthroughs in identifying TNF receptor associated factor 3 as a novel critical component of the cellular response to viral infection, involving the upregulation of type I interferon, and went on to show a surprising role for this pathway in enhancing susceptibility to bacterial infections, such as Listeria monocytogenes [1, 2, 3, 4]. He returned to Boston and completed his training in internal medicine at Brigham and Women's Hospital and a Medical Oncology Fellowship at Dana‐Farber/MGH. He then completed his postdoctoral training in the Bardeesy laboratory and stayed on faculty at MGH before moving to Fred Hutch to establish his independent lab in the fall of 2016.

Shoop entered the field of cholangiocarcinoma at a very critical time, when the genetic landscape of intrahepatic cholangiocarcinoma (ICC) began to be unveiled. Actionable mutations in isocitrate dehydrogenase (IDH) 1/2 and fusions in fibroblast growth factor receptor 2 (FGFR2) were discovered. However, the disease was understudied in the laboratory compared with other tumor types and had a paucity of model systems for preclinical and basic science investigations. Shoop was caring for a young patient with cholangiocarcinoma whose tumor harbored a mutation in IDH1. This inspired him to embark on a quest in his post‐doctoral fellowship to further understand the molecular and cell biological mechanisms by which IDH1 mutation promotes cholangiocarcinoma and to develop effective treatments for patients carrying IDH mutations. Subsequently, he successfully developed a novel genetically engineered mouse model of IDH‐driven malignancy [5], and eventually, his work from this mouse model, combined with other tools, led to the discovery that IDH mutations were indeed causing carcinogenesis by interfering in the cell's normal development—essentially causing the cells to persist in a stem cell‐like state instead of developing into the specialized liver cells they were intended to be. This state put these cells on a hair trigger. Any nudge, such as exposure to a toxin or the presence of a mutation in another gene, could set them off into the uncontrolled multiplication, which is the hallmark of cancer.

His work elegantly demonstrated that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of oncometabolite 2‐hydroxyglutarate and suppression of Hepatocyte nuclear factor‐4‐alpha (HNF‐4α), a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF‐4α silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and KRAS mutations, genetic alterations that coexist in a subset of human ICCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic ICC. Shoop would be gratified to know that the first IDH1 inhibitor, ivosidenib, improves the progression‐free survival in patients with advanced cholangiocarcinoma who have an IDH1 mutation and that treatment‐induced differentiation changes correlate with clinical benefit [6].

He also recognized the need for human patient‐derived ICC models to help guide therapeutic development, leading him to participate in joint efforts in generating cholangiocarcinoma cell lines. Using a large panel of ICC cell lines and collaborating with Cyril Benes to conduct high‐throughput drug screens, he discovered that IDH mutant ICC cells exhibit a striking response to the multikinase inhibitor dasatinib [7]. This observation led to the design of a clinical trial using dasatinib for patients with advanced cholangiocarcinoma whose tumors harbored the IDH1/2 mutations. While his work on IDH mutations was progressing, it became evident that another target, FGFR2, is also very relevant for therapeutic intervention in cholangiocarcinoma, and early results from a phase II trial with infigratinib (BGJ398) displayed encouraging efficacy in patients with FGFR2 fusion‐positive ICC, but the durability of response was limited in some patients. We embarked on a translational team effort trying to dissect the molecular basis for acquired resistance to infigratinib via integrative genomic characterization of cell‐free circulating tumor DNA, primary tumors, and metastases. We were able to demonstrate that polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism, and this finding may guide the development of future therapeutic strategies to overcome the resistance [8]. Because of his scientific acumen, strong organization skill, and being a physician scientist with strong appreciation of the clinical relevance, Shoop was instrumental and served as the key catalyst for the completion of this project.

In addition to his accomplishment in basic and translational science, Shoop was also a passionate clinician with great clinical instinct and superb skills. He enjoyed being a junior attending physician and would spend long hours with residents and fellows while on inpatient service. His soft voice and gentle demeanor complemented his intellectual firepower and clinical skills. Shoop was one of the few people whom we have met who was truly gifted both in the lab and in the clinic. He could tackle the problems at ease both on the bench and in the clinic. He could also think of the clinical research questions and engage the right people to solve the problem. In collaboration with Gabriel Brooks and Charlie Fuchs, through analyzing Surveillance, Epidemiology and End Results data, he was able to demonstrate the increasing incidence of ICC over a 40‐year period [9].

A brilliant young man with a humble demeanor. An inspiring mentor and teacher who continues to serve as a role model. A prolific physician‐scientist who was always generous to his colleagues with his expertise and time. A devoted son. The loving husband of Sita, a cancer biologist, and father of Jothin, age 3. The cholangiocarcinoma community has truly lost a young, talented bright star. He made several seminal contributions to the field in his short career. One could only imagine the impact he could have brought to the cholangiocarcinoma field had he continued his career. Despite his death, he will continue to inspire us to keep searching for the cure for cholangiocarcinoma.