New company created to develop neuroprotective therapies
MD Anderson and Accelerator Life Science Partners launch Magnolia Neurosciences to explore new treatments uncovered by MD Anderson's Therapeutics Discovery team.
A drug discovered and advanced by The University of Texas MD Anderson Cancer Center’s Institute for Applied Cancer Science (IACS) and the Center for Co-Clinical Trials (CCCT) inhibits a vital metabolic process required for cancer cells’ growth and survival.
IACS-10759 is the first small molecule drug to be developed from concept to clinical trial by MD Anderson’s Therapeutics Discovery team, which includes IACS and the CCCT. Therapeutics Discovery is a unique group of clinicians, researchers and drug development experts working collaboratively to create new treatment options, including small molecules, biologics, and cell-based therapies.
New data related to IACS-10759 were published in two papers in the June 11 online issue of Nature Medicine. The first paper reports the preclinical work led by Joseph Marszalek, Ph.D., head of Translational Biology for CCCT, and Emilia Di Francesco, Ph.D., associate director of Medicinal Chemistry at IACS, which resulted in the discovery of IACS-10759 and its advancement into Phase I clinical trials for acute myeloid leukemia (AML) and solid tumors. A second paper, authored by Andrew Futreal, Ph.D., chair, and Yonathan Lissanu Deribe, Ph.D., instructor, both of Genomic Medicine, describes the potential of IACS-10759 for treatment of lung cancers harboring a specific epigenetic alteration.
The pathway to discovery of IACS-10759
Metabolic reprogramming is an emerging hallmark of tumor biology where cancer cells evolve to rely on two key metabolic processes, glycolysis and oxidative phosphorylation (OXPHOS), to support their growth and survival. Extensive efforts have focused on therapeutic targeting of glycolysis, while OXPHOS has remained largely unexplored, partly due to an incomplete understanding of tumor contexts where OXPHOS is essential.
“Through a comprehensive translational effort enabled by collaboration across MD Anderson, we have identified multiple cancers that are highly dependent on OXPHOS,” said Marszalek.
This effort inspired the discovery and development of IACS-10759, a potent and selective inhibitor of OXPHOS. Its advancement to clinical trials was made possible by a multidisciplinary team of more than 25 scientists across Therapeutics Discovery.
“Through this collaborative, 18-month process, we identified and rapidly advanced IACS-10759 as the molecule for clinical development,” said Di Francesco. “We believe IACS-10759 will provide a promising new therapy for cancer patients.”
The pre-clinical research conducted by IACS and CCCT led to an ongoing first-in-human Phase I clinical trial, launched in October 2016, evaluating IACS-10759 in AML, led by Marina Konopleva, M.D., Ph.D., professor, and Naval Daver, M.D., associate professor, both of Leukemia. A second Phase I trial in solid tumor indications, started in November 2017, is led by Timothy Yap, M.D., Ph.D., associate professor of Investigational Cancer Therapeutics.
IACS-10759’s potential for clinical study of mutant lung cancers
IACS-10759 was evaluated in pre-clinical studies for treating lung cancers harboring mutations in the SMARCA4 gene, which render tumors sensitive to the drug due to an increased dependence on OXPHOS for survival.
SMARCA4 is a component of a chromatin modeling complex called SWI/SNF, which plays a vital role in gene expression. The study team’s analyses showed SMARCA4 mutant cells have enhanced oxygen consumption and increased respiratory capacity, making them susceptible to treatment with an OXPHOS inhibitor like IACS-10759.
“Our findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against cancers with SWI/SNF-mutant tumors,” said Lissanu Deribe. “Through multidisciplinary studies of new agents like IACS-10759, we aim to accelerate the availability of enhanced therapies for our patients.”
Marszalek and Di Francesco Team Members and Funding Sources:
MD Anderson study team members included: Jennifer Molina, Ph.D.; Yuting Sun, Ph.D.; Marina Protopopova, Ph.D.; Sonal Gera; Madhavi Bandi, Ph.D.; Christopher Bristow, Ph.D.; Edward Chang, Ph.D.; Angela Deem, Ph.D.; Ningping Feng, Ph.D.; Guang Gao; Jason Gay; Virginia Giuliani, Ph.D.; Jing Han, Ph.D.; Tin Khor, Ph.D.; Timothy Lofton; Mikhila Mahendra; Robert Mullinax; Michael Peoples; Thomas Shi; Melinda Smith;; Carlo Toniatti, M.D., Ph.D.; Giulio Draetta, M.D., Ph.D.; and Timothy Heffernan, Ph.D., all of CCCT; Timothy McAfoos, Ph.D.; Jennifer Bardenhagen; Christopher Carroll, Ph.D.; Jason Cross, Ph.D.; Barbara Czako, Ph.D.; Mary Geck Do, Ph.D.; Jennifer Greer; Sha Huang; Yongying Jiang, Ph.D.; Zhijun Kang; Gang Liu, Ph.D.; Pietro Morlacchi, Ph.D.; Alessia Petrocchi; Jay Theroff; Quanyun Xu, Ph.D.; and Philip Jones, Ph.D., all of IACS; Naval Daver, M.D.; Lina Han, M.D., Ph.D.; Helen Ma; Polina Matre, Ph.D.; Yoko Tabe, M.D., Ph.D.; Qi Zhang, Ph.D.; and Marina Konopleva, M.D., Ph.D., all of Leukemia; Gheath Al-Atrash, D.O., Ph.D.; and Stefan Ciurea, M.D.; of Stem Cell Transplantation and Cellular Therapy; Caroline Carrillo; Verlene Henry; John Frederick de Groot, M.D.; and Jian-Wen Dong, all of Neuro-Oncology; Sergej Konoplev, M.D., Ph.D., of Hematopathology; Jeffrey Ackroyd; Yu-Hsi Lin; and Florian Muller, Ph.D.of Cancer Imaging Systems; Jaime Rodriguez-Canale, M.D., of Translational Molecular Pathology; and Ronald DePinho, M.D. of Cancer Biology. Other participating institutions included The University of Texas at Austin; Cambridge University, U.K.; Agilent Technologies, Inc., Lexington, Mass.; Beth Israel Medical Center and Harvard Medical School, Boston; and the Juntendo University School of Medicine, Tokyo.
The studies were funded by MD Anderson’s Center for Co-Clinical Trials, Institute for Applied Cancer Science, the Glioblastoma Moon Shot™, and the Myelodysplastic Syndromes and Acute Myeloid Leukemia Moon Shot™, all part of the MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.
The studies were also supported by the Cancer Prevention and Research Institute of Texas (RP140218, RP140612); the American Cancer Society (RSG1514501CDD); the American Association for Cancer Research (13-90-25); the National Institutes of Health (P50CA12700107); the Sheikh Ahmed Bin Zayad Al Nahyan Center for Pancreatic Cancer; the Leukemia and Lymphoma Societies Therapeutic Accelerator Program; the Medical Research Council (U105663141).
Futreal and Lissanu Deribe Team Members and Funding Sources
MD Anderson study team members included Christopher Terranova, Ph.D.; Fatima Khan; Juan Martinez-Ledesma, Ph.D.; Chia-Chin Wu,Ph.D.; Claudia Reyes; Qian Peng; Akira Inoue, M.D., Ph.D.; and Kunal Rai, Ph.D., all of Genomic Medicine; Yuting Sun, Ph.D.; Jason Gay; Guang Gao, Ph.D.; Robert Mullinax; Tin Khor, Ph.D.; Ningping Feng, Ph.D.; Frederick Robinson; and Joseph Marszalek, Ph.D., all of IACS; Yu-Hsi Lin; and Florian Muller, Ph.D., of Cancer Systems Imaging; Veena Kochat, Ph.D., of Surgical Oncology; Chang-Gong Liu, Ph.D., of Experimental Therapeutics; Cesar Moran, M.D., of Pathology; Jing Wang, of Bioinformatics and Computational Biology; Bingliang Fang, Ph.D.; and Vali Papadimitrakopoulou, M.D., of Thoracic, Head and Neck Medical Oncology; and Ignacio Wistuba, M.D., of Translational Molecular Pathology.
The University of Texas MD Anderson and Ipsen, a global biopharmaceutical group, today announced a global licensing and joint development agreement for a pre-clinical oncology drug candidate discovered by researchers in MD Anderson’s Institute for Applied Cancer Science (IACS).
MD Anderson will progress the drug candidate through Phase I clinical development with Ipsen being responsible for further global development and commercialization.
“We believe this partnership has the potential to deliver a new therapeutic option to our patients,” said Stephen Hahn, M.D., chief medical executive at MD Anderson. “This focus on accelerating the development of efficient treatments is vital to our mission of ending cancer and to providing the very best care we can to those who need it most.”
MD Anderson and Ipsen also will collaborate to conduct additional pre-clinical studies to further explore the potential of the drug candidate’s mode-of-action and expanded indications. The detailed terms of the agreement, including development and commercial milestones and royalties, have not been disclosed.
Cancer and Alzheimer’s both are age-related diseases, but people who get one are less likely to get the other, says MD Anderson scientist Jim Ray, Ph.D.
“It’s true – people who have Alzheimer’s are less likely to develop cancer, and people who’ve had cancer are less likely to get Alzheimer’s,” says Ray, who heads Neuroscience Research at MD Anderson’s Institute for Applied Cancer Science.
Ray and colleagues think cancer and Alzheimer’s are opposite ends of the aging spectrum.
“In cancer, cells that are supposed to die won’t; and in Alzheimer’s, cells that are supposed to live don’t. Thinking about these diseases this way creates a tremendous opportunity for both fields,” he says.
Ray leads the Neurodegeneration Consortium, a multidisciplinary team of researchers from MD Anderson, Baylor College of Medicine and the Massachusetts Institute of Technology. The consortium was launched in 2012 with a $25 million gift from the Robert A. and Renee E. Belfer Family Foundation to better understand the underlying biology of Alzheimer’s disease and turn that knowledge into effective therapies for patients. The development of new, beneficial therapies has been rare, Ray says, but he’s inspired by the cancer care successes he’s seen at MD Anderson.
“It’s been 14 years since an Alzheimer’s drug was approved by the Food and Drug Administration, and even at that, the drugs we have don’t slow the disease,” he says. “In contrast, new cancer drugs are being approved on what seems like a monthly basis. Being at MD Anderson gives those of us conducting Alzheimer’s research an important opportunity to learn from that success.”
One way that cancer research may help Alzheimer’s patients is through the study of chemobrain, a common side effect of chemotherapy that causes problems with thinking and short-term memory.
“It’s projected there will be more cancer survivors with chemobrain than Alzheimer’s patients in a few years,” Ray says. “We have to find ways to promote healthy brain aging and protect the nervous system from the damaging effects of chemotherapy.”
The collaborative nature of the Neurodegeneration Consortium promises to speed up such discoveries by sharing promising findings across its three institutions.
And continued support is helping to fund the work. The Belfer Foundation followed up its initial gift with another $3.5 million in 2015. And in 2016, the M.D. Anderson Foundation has given $500,000 to the consortium. In addition, support from MD Anderson donors has totaled more than $25 million.
"At IACS, our singular goal is to provide patients
access to novel therapies, and along the way do this in a
cost-effective way. It’s a matter of accelerating meritorious
programs, while reaching rapid decisions to stop “no-go,” ineffective
projects before making large expenditures of money, time and other
What we do in oncology drug discovery really counts. I remember reading a blog a few years ago when I was at Merck that really drove this point home for me. The post was written by the husband of a patient who was responding to a drug I’d developed, the PARP inhibitor niraparib. He shared a sense of hope and encouraged others to join the clinical trial.
That day was special. It showed me that what we do, creating more treatment opportunities, makes a difference in the lives of patients and their families everywhere. I want to do that again.
None of this would be possible without philanthropy. The generosity of donors who believe in our work enables us to execute on projects of great magnitude. It gives us resources to determine where those medicines are going to be effective and get them into patient use at MD Anderson and across the world.
Engineering all the necessary properties for a single molecule to be effective in patients is a challenging process that requires multiple skill sets, with collaboration and teamwork across many disciplines. We’re unique in the way we embed drug discovery experts within MD Anderson’s world-class infrastructure, collaborating with physician-scientists and clinical researchers to move forward programs that are going to be really impactful.
The hard work of the talented cross-functional teams at IACS and MD Anderson’s Center for Co-Clinical Trials is what makes things happen. The team spirit across the group is phenomenal. I hope our collaborative effort becomes the standard for moving medicines more quickly and effectively through clinical development and getting them to the right patients much earlier."
To learn more about Philip Jones, Ph.D., visit his faculty profile.
The University of Texas MD Anderson Cancer Center celebrates the five-year anniversary of its Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives. Launched in the fall of 2012, the program already has yielded notable discoveries across the spectrum of cancer care, including prevention, early detection and treatment, and has inspired philanthropic support totaling more than $451 million.
“With its unique infrastructure and team-science approach, the Moon Shots Program is well-positioned to continue translating discoveries into the patient care setting for many years to come,” said Marshall E. Hicks, M.D., president ad interim. “We have only begun to realize the successes of the program.”
First inspired by MD Anderson’s fourth full-time president Ronald A. DePinho, M.D., the program established focused, multidisciplinary teams of clinicians and researchers tasked with developing comprehensive approaches to improving the lives of patients and reducing cancer mortality. Each component of the program undergoes regular internal and external peer-review to prioritize and direct ongoing efforts, focusing on those most likely to have significant, rapid impact for patients.
Beginning with six Moon Shots™, the program was expanded in 2015 for a total of 13 disease-focused initiatives. The Moon Shots Program also established 10 platforms, which provide unique expertise, technical support and novel infrastructure to support the program’s team science approach and accelerate the translation of data and discoveries for patients’ benefit. Philanthropic funding goes directly to support these areas of priority research and program infrastructure.
MD Anderson’s Moon Shots Program also served as an inspiration for the national Cancer Moonshot, which works toward the same goal, combining innovation and collaboration to make therapies available to more patients on a national scale. Two MD Anderson faculty serve on the Blue Ribbon Advisory panel to the national Cancer Moonshot, providing guidance and recommendations to the national effort.
Novel therapeutic approaches highlight program achievements
“Our singular vision of improving patient care has catalyzed our teams toward novel discoveries that, quite simply, would not have occurred without such focus,” said Giulio Draetta, M.D., Ph.D., co-leader of the Moon Shots Program, senior vice president, Discovery and Platforms and chief academic officer ad interim. “In five years, we have made notable advances for patients – most of which would not have been possible without the Moon Shots Program.”
Some of those accomplishments include:
- The Institute for Applied Cancer Science (IACS), a Moon Shots platform, has advanced a novel drug from discovery to clinical trials for patients with acute myeloid leukemia (AML) in collaboration with the Myelodysplastic Syndromes and Acute Myeloid Leukemia Moon Shot™. The drug, which disrupts energy production in cancer cells, will soon advance to clinical trials in patients with solid tumors. The entire development pipeline, from laboratory discovery through clinical trials, has been managed exclusively by the Moon Shots Program, which made possible the accelerated translation to the patient care setting in fewer than five years.
- The Lung Cancer Moon Shot™ has identified and resurrected an abandoned targeted therapy, poziotinib, for treating a rare group of lung cancer patients with specific treatment-resistant mutations. These patients, who previously had no effective treatment options, are seeing significant response rates in current phase II clinical trials. The pre-clinical discovery, testing, and current clinical trials were catalyzed by multidisciplinary efforts and platform support with the goal of meeting this unmet need in lung cancer patients.
- The Melanoma Moon Shot™ has opened clinical trials to evaluate neoadjuvant, or pre-surgical, treatment for high-risk patients with melanoma who would otherwise undergo surgery. Neoadjuvant therapy is a standard practice in other cancers, such as breast, but this approach was not previously feasible in melanoma due to a lack of active therapies. These trials will advance insights on the best approaches to treating patients after surgery. Additionally, using Moon Shot platforms, deep analyses of patient samples from these trials are being carried out to better understand why treatments do or do not work for all melanoma patients and guide new trial development.
Primed for increasing impact
“We have made great strides in five years, but perhaps the most important achievement is the foundation upon which current and future program discoveries will be made and lives saved,” said Andy Futreal, Ph.D., chair of Genomic Medicine and co-leader of the Moon Shots Program. “With this infrastructure, our tremendous teams of scientists, together with collaborators here and abroad, are learning more each day from the very individuals we remain committed to helping – our patients.”
The research platforms, which work across the Moon Shots, continue to advance therapies to the clinic and evaluate patient data to refine clinical strategies, ensuring patients receive the best care specific to their cancer.
The APOLLO platform is performing large-scale analysis of patient samples over time, generating novel data to better understand how tumors evolve resistance to certain treatments, making cancers more predictable and easier to treat. This platform is harnessing the power of big data and sharing across disciplines to inform better care of patients with all cancer types.
IACS is advancing multiple novel drugs toward the clinic, with the next expected to enter clinical trials in 2018. Additionally, the immunotherapy platform will continue advancing immune-based therapies to make this game-changing treatment available to more patients.
Currently, there are more than 150 clinical studies at MD Anderson that are being accelerated as a result of the Moon Shots Program, investigating both novel drug compounds as well as new approaches to improve the effectiveness of existing drugs.
The Moon Shots Program also is committed to advancing evidence-based cancer prevention and control practices, which have the potential to prevent up to 50 percent of cancers in future generations. The cancer prevention and control platform has established a range of targeted initiatives designed to advance early detection approaches, spread the use of actions known to reduce cancer risk, and improve access to screening and prevention services. Moon Shots experts also have served as educational resources for legislators across the country on policies related to cancer prevention and control.
“The Moon Shots Program is an extraordinary platform for team-based science that has inspired donor support for transformative research that otherwise may not have been funded,” said Peter WT Pisters, M.D., incoming president of MD Anderson. “We have an obligation to lead in cancer prevention and control while working to accelerate improvements in patient outcomes – all of which is possible through the Moon Shots Program and MD Anderson’s commitment to Making Cancer History®.”
The University of Texas MD Anderson Cancer Center and BridgeBio Pharma today announced the launch of Navire Pharma, a biopharmaceutical company aimed at developing novel small-molecule inhibitors of a tyrosine-protein phosphatase called SHP2 for genetically driven and treatment-resistant cancer.
BridgeBio has committed $30 million and a team of senior business managers to the company, while MD Anderson, through its Institute for Applied Cancer Sciences (IACS), provides intellectual property and an oncology drug development team to advance SHP2 inhibitors toward clinical studies.
SHP2, encoded by the PTPN11 gene, links growth factor signaling with the downstream RAS/ERK/MAPK pathway to regulate cell growth and division. Over-activity of this pathway, often driven by distinct gene mutations, causes or contributes to many human cancers. Inhibiting SHP2 offers a new approach to treat tumors relying on this pathway.
Shafique Virani, M.D., joins BridgeBio as CEO in residence, and will serve as CEO of Navire. Virani was most recently officer and vice president of Business Development, Licensing, and M&A at Roche/Genentech where he assumed several leadership roles across the globe over 13 years.
“Navire’s compounds potently bind SHP2 and prevent activation of the protein, blocking its ability to promote tumor growth,” said Virani. “Directly inhibiting SHP2 could provide patients and physicians a new, transformative approach to treat RTK-driven cancers at their source.”
Navire Pharma’s lead compounds were discovered and developed by the IACS team led by Phil Jones, Ph.D., executive director and head of drug discovery at IACS, together with Benjamin G. Neel, M.D., Ph.D., director of the Laura and Isaac Perlmutter Cancer Center at New York University (NYU).
“Resistance mechanisms that cause many patients to stop responding to therapy rely on SHP2 activity,” said Jones, a scientific co-founder of Navire. “Our ‘molecular glue’ inhibitory approach inactivates SHP2 and could help overcome these resistance pathways.”
SHP2 also suppresses T-cell activity against growing tumors through regulation of the adaptive immune response by binding to PD-1 and dephosphorylating CD28 and the protein LCK. SHP2 inhibition may relieve this negative effect, enhancing the patient’s immune response to fight cancer proliferation.
“SHP2’s role in oncogenic signaling has been known for decades, but effective approaches for inhibiting the protein were only recently discovered,” said Neel, Navire scientific co-founder and chairman of the company’s scientific advisory board. “These novel approaches have demonstrated compelling efficacy in pre-clinical disease models, which we hope will translate into benefit for patients.”
Other members of Navire’s scientific advisory board, comprised of leaders in cell signaling and hematological and solid tumors, include:
- Kwok Kin-Wong, M.D., Ph.D., chief of Hematology and Medical Oncology, NYU
- Scott Kopetz, M.D., Ph.D., associate professor, Gastrointestinal Medical Oncology, MD Anderson;
- Frank McCormick, Ph.D., director of the University of California, San Francisco (UCSF) Cancer Center and associate dean of the UCSF School of Medicine, and co-founder, Onyx Pharmaceuticals;
- Lillian Siu, M.D., professor of Medicine, Princess Margaret Cancer Centre, Toronto.
BridgeBio also has added pharmaceutical and biotechnology executives to the Navire team, including Uma Sinha, Ph.D., and Brian Metcalf, Ph.D., who together have advanced more than 30 drug candidates into human trials, and have brought nine safe and effective drug products to market. The BridgeBio team will closely collaborate with MD Anderson through IND filing and prosecute subsequent clinical trials.
“Navire combines MD Anderson’s clinicians and drug development scientists with our veteran biotechnology team to create a focused organization to develop SHP2-targeted therapies,” said Neil Kumar, Ph.D., chief executive officer of BridgeBio Pharma. “Together, we aim to bring these novel treatments to patients at the soonest possible opportunity.”