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!
Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel
Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences