The Johns Hopkins Kimmel Cancer Center and the Departments of Gynecology/Obstetrics, Neurosurgery and Pathology have been awarded more than $7.8 million for novel, multicenter projects designed to intercept and find cures for several deadly cancers, including pancreatic cancer, ovarian cancer, and the brain cancer known as glioblastoma.
The work is being funded by the cancer research foundation Break Through Cancer as part of a $50 million, three-year effort for teams across five cancer research centers. The other centers are Dana-Farber Cancer Institute in Boston; Memorial Sloan Kettering Cancer Center in New York; Koch Institute for Integrative Cancer Research at MIT, Cambridge, Mass.; and the University of Texas MD Anderson Cancer Center in Houston.
“We are grateful to Break Through Cancer for funding these innovative new avenues of research, which could help us find novel treatments or management approaches for some devastating cancers,” says William Nelson, M.D., Ph.D., director of the Johns Hopkins Kimmel Cancer Center and chairman of the board for Break Through Cancer. “Their model, combining forces across several leading comprehensive cancer centers, we hope will produce exciting results.”
One project will investigate how to intercept ovarian cancer before it occurs. Many high-grade, serous ovarian cancers – the most common and lethal type of ovarian cancer – have been found to originate in the fallopian tubes, explains Ie-Ming Shih, M.D., Ph.D., director of the TeLinde Gynecologic Pathology Laboratory in the Department of Gynecology and Obstetrics and co-director of the Women’s Malignancies Research Group at the Johns Hopkins Kimmel Cancer Center, and Rebecca Stone, M.D., director of the Kelly Gynecologic Oncology Service, Department of Gyencology and Obstetrics. Data published last month show that prophylactic removal of the fallopian tubes may substantially decrease the general population risk for ovarian cancer.
As fallopian tubes have no known life-essential function after women have finished child-bearing, investigators will examine the safety and feasibility of expanding fallopian tube removal as a primary cancer prevention strategy to women beyond those having gynecologic surgery. There is tremendous opportunity to offer this to women at the time of other planned abdominal surgeries, such as hernia repair or gallbladder removal. Investigators then can advocate for health insurance coverage of preventive fallopian tube removal and create educational materials for surgeons and patients.
Researchers also will work to create noninvasive imaging methods to improve and streamline the detection and harvesting of early cancerous lesions in the fallopian tubes; identify new biomarkers that can be used to advance ovarian cancer screening; and apply new technologies for detecting and analyzing pre-cancers. These include “OvaSeek,” a system to rapidly image fallopian tubes that have been surgically removed, and the “iCollector” to harvest living cells from fallopian tube lesions. Additionally, the group will look to compile an ovarian “precancer atlas” using molecular analyses of minuscle precancerous fallopian tube lesions obtained from participating cancer centers.
Other Johns Hopkins investigators on this project are Bert Vogelstein, M.D., Clayton Professor of Oncology; Howard Hughes Medical Institute Investigator and director of the Ludwig Center for Cancer Genetics and Therapeutics, who will serve as a research advisor on this project, Nickolas Papadopoulos, Ph.D., Tian-Li Wang, Ph.D., director of the Molecular Genetics Laboratory (MOLGEN) of Female Reproductive Cancer; Leslie Cope, Ph.D., a bioinformatician; and members of MOLGEN lab.
The grant is funding three additional lines of research:
Targeting Minimal Residual Disease in Ovarian Cancer – A key factor underlying poor ovarian cancer cure rates is the ability of cancer cells that are resistant to chemotherapy to persist after therapy. This minimal residual disease (MRD) is clinically undetectable and represents the “seed” that manifests as a cancer recurrence. The main approach to slow recurrence has been to place patients on so-called maintenance therapies – medications to try to prevent cancer from reappearing.
This project, led by Stephanie Gaillard, M.D., Ph.D., director of early phase clinical trials in gynecologic cancer, Elana Fertig, Ph.D., associate cancer center director and division director of Quantitative Sciences and co-director of the Convergence Institute; and Christopher VandenBussche, M.D., Ph.D., aims to develop new capabilities for understanding and targeting MRD. Researchers will study blood biopsies to detect minute levels of residual cancer DNA in the blood after surgery is complete, and use “second-look laparoscopies” – surgeries in which MRD cells can be harvested and studied-to study these cells’ properties. These investigations could uncover novel immune and targeted therapies for MRD.
Additionally, the team will partner with drug companies developing new therapeutics, using MRD as a clinical endpoint to watch. Finally, the team will grow and treat laboratory models of disease that, may be used to help predict which patients will and will not respond to new therapies.
Conquering KRAS in Pancreatic Cancer (in partnership with the Lustgarten Foundation) – The key driver of pancreatic ductal adenocarcinoma are mutations in a gene called KRAS. Many cells in the body need KRAS to function; however, several promising new therapies in development target only the mutant form of KRAS.
In this project, researchers will integrate clinical and laboratory approaches to understand why tumor cells become resistant to KRAS inhibition, and how to use these new drugs in combination with other agents. The primary goal is to develop effective combination therapy strategies to target KRAS in pancreatic cancer through preclinical studies and human clinical trials. The team will develop pharmaceutical partnerships to accelerate the translation of new KRAS inhibitors into effective drugs.
Johns Hopkins investigators working on this project are Nilo Azad, M.D., co-director of cancer genetics and epigenetics; Jacquelyn Zimmerman, M.D., Ph.D.; Elizabeth Thompson, M.D., Ph.D.; Katrina Purtell, R.N., clinical research nurse manager; Elana Fertig, Ph.D.; associate cancer center director and division director of Quantitative Sciences and co-director of the Convergence Institute; and Hao Wang, Ph.D., associate director of the quantitative sciences division and director of the biostatistics shared resource.
Revolutionizing GBM Drug Development Through Serial Biopsies – New therapeutics for glioblastoma have been stunted after several large phase III clinical trials were unsuccessful. Most cancer therapeutics fail to penetrate the tumor due to the protective effect of the blood-brain barrier. Repeat biopsies have been used in evaluating promising oncology therapies for other types of cancer but have not been considered for brain tumors because of safety concerns.
Through this project, researchers will assess the safety and feasibility of a carefully performed series of biopsies. They also will work to evaluate blood and cerebrospinal fluid samples, so-called “liquid biopsies,” for molecular or other markers to indicate a cancer treatment is working. In addition, investigators will try to understand how the immune response is blocked by glioblastoma tumor cells.
Johns Hopkins investigators working on this project are Chetan Bettegowda, M.D., Ph.D., the Jennison and Novak Families Professor of Neurosurgery and Vice Chair of Research for Department of Neurosurgery; Matthias Holdhoff, M.D., Ph.D.; Charles Eberhart, M.D., Ph.D., director of neuropathology and ophthalmic pathology; and Jessica Wollett, clinical trial manager.