Therapeutics Discovery Platforms Develop Impactful Cancer Treatments
Therapeutics Discovery scientists bring clinical cancer research to the lab and use a unique model for drug development to benefit cancer patients.
The University of Texas MD Anderson Cancer Center has named Giulio Draetta, M.D., Ph. D. as chief scientific officer (CSO), a new position that champions innovation, develops strong partnerships and provides focused leadership on the science and clinical translation of research programs.
“Giulio is an accomplished physician-scientist with long-standing experience in cancer genetics and drug discovery in both academia and industry,” said Peter WT Pisters, M.D., president of MD Anderson. “This appointment continues the great work he has been doing since May 2018 when he began serving as CSO ad interim, at which time MD Anderson’s basic and translational science responsibilities were placed under a chief scientific officer. He is an outstanding researcher and scientific innovator whose exceptional breadth and depth of experiences will serve him well in this new role.”
Draetta joined MD Anderson in 2011. He has contributed through several roles, including as director of the Institute for Applied Cancer Science from 2011 to 2016. In 2013, Draetta began serving as co-leader of MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives. In 2016, he became vice president of the Therapeutics Discovery division, a unique group of clinicians, researchers and drug development experts working collaboratively to develop small molecule, biologic and cell-based therapies. He was named senior vice president for Discovery and Platforms in 2017 and later that year as chief academic officer ad interim.
Draetta’s faculty appointment is in the Department of Genomic Medicine, where he holds the endowed position of Sewell Family Chair. Prior to joining MD Anderson, he was on faculty at Dana-Farber/Harvard, where he was a Presidential Scholar, chief research business development officer and deputy director of the Belfer Institute for Applied Cancer Science at Dana-Farber Cancer Institute.
He held appointments at Pharmacia and Merck, as vice president and as worldwide head of oncology drug discovery, and he has served as an investigator at the Cold Spring Harbor Laboratory, the European Molecular Biology Laboratory in Heidelberg, Germany, and the European Institute of Oncology.
Draetta spearheaded fundamental research in the biology of the eukaryotic cell division cycle and of DNA damage induced checkpoints. His research led to the discovery of the first mammalian cyclin-dependent kinase and demonstrated that cyclin-dependent kinases and cyclins physically interact and regulate multiple cell cycle transitions in eukaryotes.
He has co-founded and led biotechnology companies that have developed into successful partnerships with several pharmaceutical companies and has headed numerous drug discovery and development programs, which led to two drug approvals.
Researchers at The University of Texas MD Anderson Cancer Center have discovered that malignant rhabdoid tumors (MRT), a rare pediatric cancer without effective treatments, may be sensitive to drugs that block the cancer cell’s ability to dispose of misfolded proteins. The findings provide a much-needed therapeutic target for these and other cancers caused by mutations in the SMARCB1 gene.
Based on these findings, published today in Cancer Cell, the researchers now are leading a Phase II clinical trial to investigate this approach in renal medullary carcinoma (RMC), a related adolescent cancer also characterized by SMARCB1 mutations.
Malignant rhabdoid tumors are aggressive pediatric cancers that generally manifest in children in the first year of life, explains Giannicola Genovese, M.D., assistant professor of Genitourinary Medical Oncology and corresponding author on the study.
“It’s somewhat fortunate that these are very rare cancers. With current treatments, the prognosis is ominous – just about one year,” said Genovese. “It’s an orphan disease, meaning it has no targeted treatments available. The current options include high-dose chemotherapy, radiation and surgery, which can cause significant developmental and neurological effects and increase the risk for secondary cancers later in life.”
Driven to answer the unmet needs for patients with MRT and other cancers caused by SMARCB1 mutations, the researchers developed a mouse model of MRT to study the disease biology and uncover vulnerabilities. The researchers created a mosaic mouse model, meaning only a subset of cells carried the mutation, to study the loss of SMARCB1 in specific cells and tissues in the mice.
“Using an embryonic mosaic approach, we were able to overcome current limitations in technology and create a model that faithfully mimics features of human MRT,” said Alessandro Carugo, Ph.D., institute research scientist at the Institute for Applied Cancer Science (IACS). “We demonstrated, in our model, that SMARCB1-deficient cells are characterized by dysregulation of protein synthesis and disposal, causing them to be loaded with misfolded protein aggregates.”
Excess or misfolded proteins can be toxic to the cell, so the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress response pathways are normally activated to clear protein waste. However, with loss of SMARCB1, these pathways were hijacked and incorrectly activated to account for protein accumulation in malignant cells.
The researchers also discovered that the cancer cells were able to survive this buildup through the activity of p53, a tumor suppressor that normally acts to block tumor growth. In contrast, SMARCB1-deficient cells appear to activate p53 for a survival advantage and, in fact, may benefit from chemotherapy treatments, which further stimulate p53 activity.
“TP53 is the most frequently mutated gene in cancer, but it does not appear to be mutated in MRT,” said Carugo. “We were excited to learn that, here, it’s functional because the cells need p53 to counterbalance the protein accumulation associated with SMARCB1 loss.”
Recognizing the mis-regulated protein pathways as a potential vulnerability, the researchers leveraged the capabilities of MD Anderson’s Therapeutics Discovery platforms, including IACS, to design a drug combination to test this hypothesis. The Therapeutics Discovery division is a unique group of clinicians, researchers and drug discovery scientists working to develop innovative treatment options, inspired by the needs of patients and guided by the expertise of MD Anderson physicians.
The researchers targeted two mechanisms important for clearing protein waste, known as autophagy and proteasome degradation. Blocking these in the mouse model led to complete tumor regression, and the results were further confirmed in mouse transplants and cell lines derived from human MRT.
The findings of this study led the researchers to initiate a Phase II clinical trial testing a proteasome inhibitor in combination with chemotherapy for patients with RMC. This rare form of kidney cancer, also driven by SMARCB1 mutations, affects adolescents and young adults, primarily African Americans with the sickle-cell trait. The trial also is available for adolescents and adults who develop MRT in their kidney.
“This is the first trial designed specifically for SMARCB1-mutant RMC. These are rare cancers that don’t respond to the standard of care for other kidney cancers,” said Genovese. “There is a need for new therapies for treating these patients. I think we’ve developed a good platform for discovery, to provide options for these patients and hope for the families as well.”
The researchers are working to expand the trial in the future to include pediatric MRT and other SMARCB1-related cancers. In addition, the Therapeutics Discovery team will continue to investigate new medicines that may benefit these patients in the future.
Genovese is corresponding author of the study together with Nizar Tannir, M.D., professor of Genitourinary Medical Oncology, and Giulio F. Draetta, M.D., Ph.D., chief science officer ad interim and senior vice president of Therapeutics Discovery. A complete list of authors involved with the study can be found with the full article. The authors declare no conflicts of interest.
The study was supported by the Conquer Cancer Foundation Young
Investigator Award, the Kidney
Cancer Association Young Investigator Award, the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, the Pancreatic Cancer Action Network, the Italian Foundation for Cancer Research and Italian Association for Cancer Research (FIRC-AIRC), the Ransom Horne, Jr. Professorship for Cancer Research, the Barbara Massie Memorial Fund and the Cancer Prevention and Research Institute of Texas (RP170722).
DNA damage response (DDR) inhibitors, such as poly (ADP-ribose) polymerase (PARP) inhibitors, are a type of targeted therapy used to treat cancers with existing defects in DNA repair, such as BRCA mutant cancers.
DDR inhibitors block critical DNA repair pathways that these cancers rely on to repair their DNA as they grow and divide. Other important DDR players being targeted by researchers are ataxia telangiectasia and Rad3-related (ATR) kinase, ataxia telangiectasia mutated (ATM) kinase, Wee1 kinase, checkpoint kinase 1 and 2 (CHK1/2) and DNA-dependent protein kinase (DNA-PK).
“It’s an extremely important area of research,” says Timothy Yap, M.D., Ph.D., associate professor of Investigational Cancer Therapeutics and associate director of translational research of the Institute for Personalized Cancer Therapy. Yap also is medical director of the Institute for Applied Cancer Science, a research platform that supports MD Anderson’s Moon Shots ProgramTM, which is a collaborative effort to accelerate the translation of scientific discoveries into clinical advances that save patients’ lives.
With dozens of Phase I clinical trials underway, Yap and his team are working to discover the next big breakthrough with DDR inhibitors, so that more patients can benefit and those who are responding experience longer, deeper responses.
Proven success with PARP inhibitors
In recent years, PARP inhibitors have emerged as a new therapy for a few advanced cancers for which there have been limited treatment options. The PARP inhibitors olaparib, niraparib and rucaparib are approved by the Food and Drug Administration (FDA) for patients with BRCA-related and non-BRCA–related advanced ovarian cancer in the advanced and maintenance settings, respectively; and thanks to the EMBRACA trial, the PARP inhibitor talazoparib was approved this past summer for patients with metastatic BRCA1/2-positive, HER2-negative breast cancer.
Despite the success of DDR inhibitors, there’s room to improve.
“We need more patients to benefit and we need deeper, more durable responses,” Yap says. “And I believe we can do that through rational combinations in selected molecular subtypes of patients.”
Advancement through combinations
As Yap describes it, the beauty of DDR inhibitors, such as PARP inhibitors, is their ability to be used in combination regimens with other therapies to improve a patient’s response.
“I see PARP inhibitors as a foundational class of drugs,” Yap says. “Like PD-1 and PD-L1 immune checkpoint inhibitors, we can build a whole program on PARP inhibitors that can work in multiple cancers and different molecular subtypes of those cancers.”
Yap is working within three different classes of combinations:
- DDR inhibitor plus DDR inhibitor — When one DDR agent, such as a PARP inhibitor, is combined with another type of DDR inhibitor, patients may be able to overcome resistance seen with DDR inhibitor monotherapies.
- DDR inhibitor plus other targeted therapies — For tumors that don’t have existing DNA repair defects, Yap and his team are inducing a “chemical BRCAness.” For example, by suppressing the BRCA protein using PI3K inhibitors, the cancer cells become susceptible to DDR inhibitors, similar to BRCA-positive tumors.
- DDR inhibitor plus immunotherapy — Studies have shown that DDR inhibitors activate the immune system. Furthermore, in a lab setting, a synergy has been noted between the two classes of drugs when they’re combined. Recently, MD Anderson researchers discovered that a combination of immune checkpoint blockade and targeted therapies that block normal DNA damage repair achieved significant tumor regression in mouse models of small cell lung cancer, suggesting a promising new approach for treating patients with this aggressive cancer.
Yap hypothesizes that there are different levels of sensitivity to these drugs within each gene mutation and that there’s also context dependency between different tumor types.
“The likelihood of a response in a BRCA1-mutant ovarian cancer and a BRCA1-mutant pancreatic cancer is unlikely to be the same,” he says. “But that’s what we’re working to find out.”
Quality of life improvements
Since DDR inhibitors are administered orally, the convenience potentially can improve patients’ quality of life.
“It’s changing how we treat patients,” Yap says.
The convenience has allowed patients from across the country to participate in these unique trials that aren’t available anywhere else. Depending on the trial, participants may have to come to MD Anderson to see their care team every two to three weeks for evaluation.
Myelosuppression, GI tract rank high as potential side effects
The most commonly seen side effect with DDR inhibitors has been myelosuppression, resulting in anemia, neutropenia and thrombocytopenia. Other commonly reported side effects are upset stomach, vomiting and diarrhea, and also fatigue.
Patients are informed about the signs of possible side effects, and they’re monitored closely. If a patient experiences an adverse event, he or she may be taken off the DDR inhibitor for a short period of time until the side effect returns to a safe and tolerable level. Side effects involving the gastrointestinal tract can effectively be treated with medications. In the case of myelosuppression, a blood transfusion may also be needed.
“It’s an exciting time for these new agents,” Yap says. “But we still have a lot to learn to reduce the toxicity, as well as widen the number of patients who are benefiting.”
The University of Texas MD Anderson Cancer Center and Accelerator Life Science Partners, a leading life science investment and management firm, today announced the launch of Magnolia Neurosciences Corporation, a company developing a new class of neuroprotective medicines, with $31 million in Series A funding. The company will develop novel therapeutics based on discoveries made by researchers in MD Anderson’s Therapeutics Discovery division, including the Institute for Applied Cancer Science (IACS) and the Neurodegeneration Consortium (NDC).
“By developing new treatments, Magnolia Neurosciences will address a critical need for patients suffering from neurodegenerative conditions, such as Alzheimer’s disease and chemotherapy-induced neuropathy in cancer patients,” said Jim Ray, Ph.D., director of the NDC. “These conditions are driven by similar biological pathways, and it is our hope that we can improve the lives of patients across disease types based upon new drug candidates discovered by the MD Anderson Therapeutics Discovery team.”
Annually, more than 700,000 Americans with cancer are treated with chemotherapy, and many experience a variety of neural and cognitive impairments as a result of their treatment. More than 200,000 patients each year will suffer from a condition known as “chemobrain,” characterized by general cognitive and memory problems, which can last for years. Additionally, roughly two-thirds of patients undergoing chemotherapy treatment develop peripheral neuropathy, in which nerve damage causes pain, numbness and tingling in the hands and feet.
The development of medicines to prevent these conditions in patients receiving chemotherapy would not only improve patients’ quality of life, but also would avoid the need for dose reductions or breaks from therapy, resulting in improved survival, explained Philip Jones, Ph.D., vice president of Therapeutics Discovery and head of drug discovery at IACS.
Neurodegenerative diseases include a range of conditions characterized by progressive deterioration of neurons in the human brain. These conditions affect millions of Americans and are largely untreatable.
The NDC is a multi-institutional initiative launched to better understand the biology of neurodegenerative diseases and translate that knowledge into effective therapeutics interventions. Established in 2012 by an inaugural $25 million gift from the Robert A. and Renee E. Belfer Family Foundation, the NDC brings researchers from Baylor College of Medicine, the Massachusetts Institute of Technology and the Icahn School of Medicine at Mount Sinai together with drug discovery and development experts from MD Anderson’s Therapeutics Discovery division.
The Therapeutics Discovery division is a unique group of more than 100 clinicians, researchers and drug discovery scientists at MD Anderson working to develop innovative treatment options, including small molecules, biologics and cell-based therapies. The goal of the Therapeutics Discovery team is to bring transformational, life-saving medicines to patients quickly, safely and effectively by working closely with patients and clinicians.
“Our team is inspired by the needs we see in our patients, and we learned from MD Anderson’s physicians that some cancer treatments can cause significant neurocognitive and neuropathy challenges for survivors,” said Jones. “Therefore, we set out to discover new therapies to combat these issues and, hopefully, a variety of other neurodegenerative conditions.”
Under the leadership of Giulio Draetta, M.D., Ph.D., senior vice president and head of Therapeutics Discovery and co-leader of MD Anderson’s Moon Shots Program™, Ray and Jones established a multi-disciplinary team of scientists to identify and advance new targeted therapies to treat neural damage, which now form the basis of Magnolia Neurosciences. Ray and Jones also will serve as members of the Magnolia Neurosciences Scientific Advisory Board.
“This project is a stellar example of the patient-focused drug development model that drives Therapeutics Discovery and exemplifies MD Anderson’s commitment to caring for our patients throughout their entire cancer journey, from diagnosis to survivorship,” said Draetta. “We’re excited to see these new therapeutics progress into clinical trials through the launch of Magnolia Neurosciences.”
Investors participating in the $31 Million Series A financing include AbbVie Ventures, Alexandria Venture Investments, ARCH Venture Partners, Eli Lilly and Company, Innovate NY Fund, Johnson & Johnson Innovation – JJDC, Inc., the Partnership Fund for New York City, Pfizer Ventures, Watson Fund, L.P., WuXi AppTec’s Corporate Venture Fund and 180 Degree Capital Corp.
The preclinical research to identify and develop the novel drug candidates being advanced by Magnolia Neurosciences was funded by the NDC, through support from the Robert A. and Renee E. Belfer Family Foundation; and IACS, part of MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.