In a significant breakthrough, investigators at Weill Cornell Medical College and the University of California, San Francisco, have been able to overcome resistance of a form of leukemia to targeted therapy, demonstrating complete eradication of the cancer in cell and animal studies.
Their study, published in the May 19 issue of Nature, shows that an investigational drug, RI-BPI, developed at Weill Cornell, in combination with the drug Gleevec shut down stem cells responsible for about one-third of acute lymphoblastic leukemia (ALL), a cancer of white blood cells that affects young children as well as older adults.
This form of ALL has the so-called Philadelphia chromosome, which is also found in chronic myelogenous leukemia (CML). But while Gleevec has greatly improved survival in CML, it has had a less dramatic effect in ALL, and most patients still die within a relatively short timeframe.
That desperate prognosis may radically change given these results, says co-senior investigator Dr. Ari Melnick, associate professor of medicine and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College, and a hematologist-oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
"I am surprised, and extremely glad, to see that RI-BPI has such strong activity in a leukemia. This opens up the possibility that the agent will have similar beneficial effects in other tumor types," says Dr. Melnick.
Dr. Melnick and his colleagues developed RI-BPI and they have shown its potent effects in non-Hodgkin's lymphoma (NHL) with no toxicity to normal cells. The drug targets the transcription factor BCL6, a master regulator of hundreds of genes that provides strong growth signals to NHL cells.
The new study demonstrated that BCL6 is also active in ALL driven by the Philadelphia chromosome (Ph+ ALL), and that a combination of RI-BPI and Gleevec virtually shuts the cancer down, says Dr. Melnick. After a long search for the source of Gleevec resistance in this form of ALL by the team at the University of California, San Francisco (UCSF), it appears that BCL6 is the fundamental mediator of that resistance, he explains. "This gives us an opportunity to target Gleevec resistance, something that has the potential to substantially improve outcomes for patients with this disease."
The UCSF research team discovered that production of BCL6 is turned on after administration of Gleevec in Ph+ ALL. UCSF investigators then initiated collaborative research with Dr. Melnick, who provided RI-BPI and conducted experiments on how BCL6 regulates genes in leukemia cells.
The UCSF team also conducted animal tests and discovered that BCL6 hits the stem cells that give rise to ALL. "These stem cells continually repopulate disease cells by making copies of themselves," Dr. Melnick says. "We believe RI-BPI counteracts the BCL6 gene regulatory program that these stem cells need to survive.
"BCL6 turns off the brakes that normally limit cancer growth, which is why Gleevec does not work in this cancer, but RI-BPI puts those brakes back on," he says.
The study also suggests that transcription factors like BCL6 may be less impervious than once thought to targeted treatment, Dr. Melnick says. BCL6 is a protein, and it "mediates its cancer-causing actions by attaching to other proteins. Traditionally, however, protein-protein interactions have been viewed as being too difficult to block with small-molecule drugs."
Although it has yet to be tested in refractory CML -- CML that has become resistant to Gleevec, which occurs in most patients over time -- it makes sense that RI-BPI could restore Gleevec sensitivity, Dr. Melnick adds.
"From this study and from the others in my lab, I have become very impressed with how reliant tumor cells are on certain proteins for their survival," he says. "If we can hit several of these brittle and dependent processes, we have the chance to eradicate cancer."
Based on this study, a clinical trial is being developed to treat children with Ph+ ALL with a combination of RI-BPI.
The study was supported by grants from the National Institutes of Health/National Cancer Institute, the Leukemia and Lymphoma Society, the California Institute for Regenerative Medicine, the William Laurence and Blanche Hughes Foundation, and an American Association for Cancer Research Stand Up To Cancer Innovative Research Grant.
The study's co-senior investigator is Dr. Markus Müschen, a professor of laboratory medicine at UCSF. The lead author is Dr. Cihangir Duy of UCSF. Co-authors include, from Weill Cornell Medical College: Dr. Leandro Cerchietti and Huimin Geng; from UCSF: Dr. Christian Hurtz, Dr. Seyedmehdi Shojaee, Dr. Srividya Swaminathan, Dr. Lars Klemm and Dr. Rahul Nahar; from Children's Hospital Los Angeles: Dr. Nora Heisterkamp, Dr. Soo-mi Kweon, Dr. Eugene Park and Dr. Yong-mi Kim; from Universitätsklinikum Hamburg-Eppendorf: Dr. Melanie Braig; from Universität Heidelberg, Klinikum Mannheim: Dr. Wolf-Karsten Hofmann; from Albert-Ludwigs-Universität Freiburg and Max-Planck-Institute for Immunobiology: Dr. Sebastian Herzog and Dr. Hassan Jumaa; from Cedars Sinai Medical Center, Los Angeles: Dr. Phillip Koeffler; from the Albert Einstein College of Medicine: Dr. Jessica Yu and Dr. Hilda Ye; and from the University of California, Los Angeles: Dr. Thomas G. Graeber.
The authors declare no competing financial interests. Weill Cornell Medical College holds a patent on RI-BPI.
The Raymond and Beverly Sackler Center for Biomedical and Physical Sciences
The Raymond and Beverly Sackler Center for Biomedical and Physical Sciences of Weill Cornell Medical College brings together a multidisciplinary team of scientists for the purpose of catalyzing major advances in medicine. By harnessing the combined power of experimental approaches rooted in the physical and biological sciences, Sackler Center investigators can best accelerate the pace of discovery and translate these findings for the benefit of patients with various medical conditions, including but not limited to cancer.
Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston, making Weill Cornell one of only two medical colleges in the country affiliated with two U.S.News & World Report Honor Roll hospitals. For more information, visit weill.cornell.edu.
Andrew Klein | EurekAlert!
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