Streamlining and translating basic science discoveries into the clinic

Jul 2 2018

To make sure that good ideas to enhance healthcare are not lost due to a lack of resources, a growing number of centers at Penn Medicine organize forums to pitch ideas to improve medical devices and technology, hold annual competitions to fund studies to improve patient care while keeping costs down, and sponsor seed grants for programs focused on patients who need individualized tailoring of their treatment. This last category is where precision medicine comes in, which is designed to enhance care for particular groups of patients, based on their genetic background, patient history, and unique diagnosis.

"Precision medicine is a young field," said David B. Roth, MD, PhD, director of the Penn Center for Precision Medicine (PCPM) and chair of the department of Pathology and Laboratory Medicine. "Our initial successes have been in the field of cancer with small numbers of patients and sophisticated technologies that are typically not available or fully integrated into clinical work flows." PCPM takes a team approach, bringing together clinicians with experts in data analysis, biomedical informatics, biostatistics, and health economics.

To promote translating basic science discoveries into the clinic, PCPM is working to expand their approach to precision medicine, project by project, disease by disease. To do this, over the last three years, the PCPM Accelerator Fund has awarded about $1.5 million to over 20 investigators in a broad array of fields, including addiction, cardiology, oncology, infectious diseases, psychiatry, and rare diseases.

PCPM recently announced their third round of recipients at their annual symposium. "Our awardees are all part of a diverse mix between emerging clinical trials and applications of new technologies that promise to be scalable and reach patients very soon," Roth said.

The eight projects that received funding in 2017, from nine Penn Medicine departments and divisions, have all made substantial progress on PCPM's promise of "providing the right treatment (or prevention) to each individual at the right time." The projects range in focus from common disorders to the rarely diagnosed and most life-threatening diseases and conditions.

• • Henry Kranzler, MD, a professor of Psychiatry, is using molecular genetic information to predict opioid dose requirements in African-American patients following hip or knee replacement surgery at Penn Presbyterian Medical Center. Kranzler's team identified a piece of DNA that's associated with an opioid receptor gene. The team is examining the genetic information and opioid dose given to each patient to make sure they are being prescribed the correct dose to manage their pain.

• • David Fajgenbaum, MD has been battling idiopathic multicentric Castleman disease (iMCD), a rare and deadly immune system disorder, since 2010. PCPM funds allowed Fajgenbaum, an assistant professor of Translational Medicine & Human Genetics and associate director of patient impact at the Penn Orphan Disease Center, to generate the preliminary data he needed to submit a grant proposal to the National Heart Lung and Blood Disorders Institute earlier this year to move his research into a clinical trial.

• • Aimee S. Payne, MD, PhD, an associate professor of Dermatology, used PCPM seed funds to complete preclinical experiments that essentially "cured" mice of a rare and potentially fatal autoimmune skin disease. By using engineered T cells, which can persist indefinitely and prevent disease recurrence, this work could transform autoimmune-related therapy in general, taking it from a strategy of chronic immune suppression to a one-time treatment. The team is now tweaking the design of the engineered T cells for human clinical trials to eliminate unwanted side effects. They plan to open human trials in 2019.

• • Daniel Herman, MD, PhD, an assistant professor of Pathology and Laboratory Medicine, has developed a machine-learning approach to screen all Penn Medicine patients' lab and patient records for evidence of primary aldosteronism, a commonly missed cause of high blood pressure that can be treated or cured by targeted medications or surgery. When fully implemented, this process will help physicians identify patients with aldosteronism and directly translate their individual health information into a regimen that will improve their blood pressure levels.

• The underlying cause of cardiomyopathy, a heart disorder that makes it harder for the heart to pump, is unknown in 75 percent of cases. Kenneth Margulies, MD, and Francis Marchlinski, MD, both professors of Cardiology, have combined better-targeted biopsies of heart tissue, more extensive analysis of that tissue, and genetic testing to characterize individual cases of cardiomyopathy to identify better treatments.

• • Robert Faryabi, PhD, an assistant professor of Cancer Biology, and Michael Feldman, MD, PhD, a professor of Pathology and Laboratory Medicine, have developed a Netflix-like algorithm to more accurately detect a class of complex mutations that occur in one in four patients with acute myeloid leukemia (AML). They built software to predict which mutations respond best to the five drugs currently being used for AML.

• • In another hard-to-treat type of cancer, Kim Reiss Binder, MD, an assistant professor of Hematology/Oncology, has designed a clinical trial for patients with pancreatic cancer whose disease has been controlled by platinum-based therapies for at least four months. This team is testing – in a two-arm clinical trial – less toxic, more sustainable therapies to use after platinum-chemotherapy toxicities set in for these patients.

• • Using a panel of existing FDA-approved drugs, Terence Gade, MD, PhD, and Junwei Shi, PhD, both from the department of Cancer Biology, with Sara Cherry, PhD, a professor of Microbiology and director of PCPM's Program for Chemogenomic Discovery, are screening hepatocellular carcinoma (HCC) tumor cells from patients to extend the limited therapeutic options for this type of cancer. In early tests, the team found that one patient's cells were sensitive to drugs commonly used to treat lung, ovarian, cervical, and pancreatic cancer, as well as multiple myeloma and lymphoma.

This overall approach to accelerating the implementation of good ideas from people on the front lines of care is starting to make a difference. For example, since 2011 Penn Medicine data scientists have been using special software to spot sepsis before it becomes a problem. Their first iteration of the program, Early Warning System 1.0, gave ED doctors a few hours lead time if a patient's vitals were heading south. Now, version 2.0 predicts sepsis about 1.5 days ahead of time.

In the same vein, using new technologies like artificial intelligence, accessing large databanks of genetic and patient data, and screening already-approved drugs for new uses, PCPM is making good on its promise of precision - to be the right center for the right treatment at the right time.