The University of Texas MD Anderson Cancer Center and Eisbach Bio GmbH today announced a strategic research collaboration to jointly discover and develop precision oncology drugs that target synthetic lethal engines key to tumor genome evolution.
The agreement aligns the drug discovery and development expertise of MD Anderson’s Therapeutics Discovery division with the innovative discovery platform and allosteric assay technology of Eisbach to generate medicines that selectively disrupt genome replication and DNA repair in cancers harboring defined genetic alterations.
“Modern genomics has revealed synthetic lethal targets in certain cancers with tumor suppressor gene mutations, and Eisbach has developed tools to pinpoint precisely where these targets are vulnerable at the molecular level,” said Adrian Schomburg, Ph.D., chief executive officer of Eisbach. “We are excited to collaborate with MD Anderson to develop innovative targeted therapies that exploit these unique vulnerabilities.”
Synthetic lethality is a phenomenon in which cancer cells with mutations in certain pathways are hypersensitive to drugs targeting related pathways. Notably, defects in certain DNA damage repair pathways – common to many cancer types – render cancer cells dependent on processes that reorganize the cancer genome.
“Cancers harboring mutations in tumor suppressor genes have been notoriously difficult to treat in the past,” said Timothy A. Yap, M.B.B.S., Ph.D., associate professor of Investigational Cancer Therapeutics and medical director of the Institute for Applied Cancer Science (IACS) at MD Anderson. “However, growing clinical evidence with PARP inhibitors demonstrates that targeting synthetic lethality is a promising strategy in certain cancer types, and we look forward to continued progress in this space.”
Eisbach and MD Anderson will leverage their complementary expertise to jointly identify targets and develop small-molecule therapies that can shut off specific epigenetic processes, thereby disrupting genome control selectively in tumor cells while sparing normal tissues. With its proprietary assay platform, Eisbach is uniquely capable of identifying and targeting molecular vulnerabilities in this machinery through allosteric mechanisms.
“Our platform identifies the unique activation mechanisms of molecular machines essential for cancer cell growth,” said Andreas Ladurner, Ph.D., chief scientific officer at Eisbach. “With this insight, we are able to develop targeted drugs that selectively interfere with the ignition of the engines that tumor cells have come to rely upon. These drugs are safe and selective by design.”
Eisbach will collaborate with the team at IACS, a drug discovery engine focused on developing novel small-molecule therapeutics. IACS is a core component of MD Anderson’s Therapeutics Discovery division, an integrated team of researchers, physicians and drug development experts working to advance impactful new therapies.
“Our Therapeutics Discovery team is committed to developing the next generation of cancer treatments that address significant unmet needs in oncology,” said Philip Jones, Ph.D., vice president of Therapeutics Discovery and head of IACS at MD Anderson. “By focusing on epigenetic machinery in our collaboration with Eisbach, we are hoping to advance additional much-needed therapeutic options that can improve patients’ lives.”
Under the terms of the agreement, Eisbach and MD Anderson will jointly determine the appropriate pathway for future development and possible commercialization on any therapies that show promise in laboratory studies.
MD Anderson has an institutional conflict of interest with Eisbach Bio GmbH through this strategic alliance and is implementing an Institutional Conflict of Interest Management and Monitoring Plan for all research related to this agreement.
The University of Texas MD Anderson Cancer Center and Schrödinger, Inc. today announced a two-year strategic research collaboration focused on accelerating and optimizing the development of Schrödinger’s WEE1 inhibitor program, an investigational therapeutic approach designed to target the WEE1 kinase.
The collaboration brings together the translational research and drug development expertise of MD Anderson’s Therapeutics Discovery division with Schrödinger’s expertise and drug development program for WEE1 inhibitors. The goal of the collaboration is to accelerate and optimize the clinical development path for Schrödinger’s WEE1 program through molecular biomarker-driven tumor type prioritization and patient stratification and to validate biomarkers to predict response or resistance to a WEE1 inhibitor. The joint team will seek to prioritize clinical studies of a WEE1 inhibitor as a single agent in selected cancer indications and in rational combinations for defined clinical subpopulations.
"We are excited to work with MD Anderson’s researchers to speed the development of our WEE1 program and potentially advance a new therapeutic option for patients," said Karen Akinsanya, Ph.D., executive vice president, chief biomedical scientist and head of discovery research and development at Schrödinger. "We have identified multiple highly selective WEE1 inhibitors with desirable drug-like properties that show strong pharmacodynamic responses and anti-tumor activity in preclinical models. We believe this profile may position our compounds as ideal candidates for applications both as monotherapy and as combination therapy partners.”
Under the preclinical collaboration agreement, Schrödinger will join forces with researchers in MD Anderson's Translational Research to AdvanCe Therapeutics and Innovation in ONcology (TRACTION) platform, which leads cutting-edge translational biology research to rapidly position new therapies for clinical trials. TRACTION is a core component of MD Anderson’s Therapeutics Discovery division, an integrated team of clinicians, researchers and drug development experts working to advance impactful therapies that address patient needs.
"Targeting WEE1, a critical gatekeeper of the cell cycle, is showing promise as a therapeutic strategy for treating certain cancers with select genetic alterations," said Timothy Heffernan, Ph.D., executive director of TRACTION at MD Anderson. “Through our collaboration with Schrödinger, we aim to identify clinically relevant patient populations that may benefit from WEE1 inhibition and to advance innovative targeted therapies that can improve their lives.”
MD Anderson and Schrödinger will jointly pursue translational studies, and Schrödinger will provide research support funding. As part of the agreement, MD Anderson is eligible to receive certain payments based on the future development and commercialization of Schrödinger’s WEE1 inhibitor compounds. Schrödinger will have sole responsibility for the development, manufacture and commercialization of all compounds and products, and sole rights to all novel intellectual property that arises from this collaboration.
WEE1 is a gatekeeper checkpoint kinase that prevents progression through the cell cycle, allowing time for DNA repair to occur before cell division takes place. Thus, inhibition of WEE1 allows for accumulation of DNA damage, triggering DNA breakage and apoptosis in tumor cells. Schrödinger is developing tight-binding, selective WEE1 inhibitors with optimized physicochemical properties designed to be well suited for combinations with other DNA damage response therapies for the treatment of a broad range of solid tumors.
The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recently published studies in basic, translational and clinical cancer research from MD Anderson experts. Current advances include new targeted therapy approaches for chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), predicting survival following follicular lymphoma treatment, understanding how AML responds to checkpoint blockade therapy, identifying disparities in colorectal cancer screening, pregnancy outcomes following surgery for early-stage cervical cancer, and the discovery of a novel SHP2 targeted therapy.
Treatment of CLL with combined targeted agents can be discontinued for patients with confirmed undetectable MRD
Combined ibrutinib plus venetoclax treatment was shown to improve outcomes for patients with chronic lymphocytic leukemia (CLL). Continuous treatment with a BTK inhibitor, like ibrutinib, provides exceptional maintenance of disease control, but time-limited treatment options are needed. The phase II CAPTIVATE trial, led by William Wierda, M.D., Ph.D., assessed minimal residual disease (MRD)-based treatment discontinuation following completion of first-line, finite-duration ibrutinib plus venetoclax treatment in patients with CLL. For patients with confirmed undetectable MRD, the reported findings showed no difference in one-year disease-free survival rate (95% for both arms) between those randomized to continue single-agent ibrutinib or placebo. The results indicate the potential and expectation for meaningful durable remission off treatment following finite-duration therapy with this regimen. Learn more in Journal of Clinical Oncology.
Combination therapy shows promise for AML expressing RUNX1 mutations
Patients with acute myeloid leukemia (AML) that expresses a RUNX1 mutation often have poorer clinical outcomes than those with wild-type RUNX1. In laboratory-based mechanistic studies led by Kapil Bhalla, M.D., AML cells expressing mutant RUNX1 were more sensitive to the protein translation inhibitor omacetaxine and the BCL2 inhibitor venetoclax. Therefore, Bhalla and colleagues explored combination therapy with omacetaxine and venetoclax or a BET inhibitor. Compared to single-agent therapy, the combination treatment showed synergistic anti-AML effects in vivo, improving survival in laboratory models. These findings suggest that omacetaxine-based combination therapies may be effective against AML with RUNX1 mutations. Learn more in Blood.
Validating disease progression as a clinical predictor of survival in follicular lymphoma
Previous trials and studies have suggested that patients with follicular lymphoma (FL) whose disease progresses within 24 months of front-line chemoimmunotherapy have poor outcomes. Christopher Flowers, M.D., and colleagues conducted a pooled analysis of 13 randomized clinical trials of FL patients to validate progression of disease after 24 months (abbreviated as POD24) and analyze it in relation to clinical outcomes. The pooled analysis found that POD24 following chemoimmunotherapy was associated with poor overall survival, and it identified clinical predictors, like elevated β2-microglobulin and high Follicular Lymphoma International Prognostic Index (FLIPI) risk score, of disease progression. These findings may be used to build future models, incorporating clinical and molecular predictors of POD24 to better predict patients’ outcomes. Learn more in Blood.
Understanding response to PD-1 blockade treatment in acute myeloid leukemia
Checkpoint blockade-based therapies tend to produce only moderate responses in patients with acute myeloid leukemia (AML). To evaluate whether biomarkers of response or resistance could be identified, a team led by Hussein Abbas, M.D., Ph.D., Andy Futreal, Ph.D., and Naval Daver, M.D., conducted paired single-cell RNA analysis and TCR profiling of bone marrow cells in patients with AML who responded and then relapsed or did not respond following azacitidine and PD1 inhibitor therapy. They demonstrated that the subsets of T cells related to AML were very heterogeneous after PD-1 blockade-based treatment; T cell repertoires expanded in patients whose disease remained stable or responded to treatment and contracted in patients whose disease was resistant to treatment. These findings indicate that adaptive T cell plasticity affects how AML responds to PD-1 blockade-based therapies and may help in developing future immune strategies for AML. Learn more in Nature Communications.
Women living in rural areas less likely to be screened for colorectal cancer
Cancer screenings have been shown to save lives, but disparities persist across certain demographics. Research has shown that cancer mortality rates remain higher in rural populations, which have higher incidences of cancer types that are preventable through regular screening, compared to urban populations. In this study, Sanjay Shete, Ph.D., and colleagues from the Rural Workgroup of the NCI Population Health Assessment in Cancer Center Catchment Areas Initiative, analyzed breast and colorectal cancer screening rates among 2,897 women from 11 states. They found significant differences in adherence to colorectal cancer screening, with 82% of women in urban areas up to date on screening, compared to 78% of women in rural areas. However, both groups were equally likely to be up to date on breast cancer screening (81%). The findings indicate an opportunity for improved public health interventions. Learn more in JAMA Network Open.
First pregnancy after fertility-sparing surgery for early-stage cervical cancer patients had higher odds of preterm delivery
Most patients with cervical cancer will be diagnosed around reproductive age, and an increasing number of women with early-stage disease seek fertility-sparing options. These surgical options — cervical conization, loop electrosurgical excision procedure (LEEP) and trachelectomy — have been widely accepted in select patients; however, because fewer than half of patients attempt to conceive, the obstetric risks have not yet been fully explored. In a population-based study, Alejandro Rauh-Hain, M.D., and a team of researchers evaluated the outcomes of the first pregnancy after fertility-sparing surgery in patients with early-stage cervical cancer. The researchers found that for women who conceived at least three months after undergoing cervical conization or LEEP for cervical cancer, the odds of preterm birth and neonatal morbidity were doubled. However, pregnancies after fertility-sparing surgery for cervical cancer did not have an increased risk of preterm birth before 32 weeks of gestation, stillbirth, cesarean delivery, growth restriction or severe maternal morbidity. Learn more in Obstetrics & Gynecology.
Novel SHP2 targeted therapy effective in early laboratory studies
The SHP2 protein (Src homology 2 domain-containing phosphatase), which sits at the intersection of multiple oncogenic signaling pathways, plays a critical role in cancer development across many tumor types. Evidence suggests that SHP2 also suppresses the anti-tumor immune response. Through an ongoing strategic collaboration, MD Anderson’s Therapeutics Discovery division and BridgeBio Pharma, Inc. are advancing SHP2 inhibitors, including the launch of a clinical trial for BBP-398 in 2020. Complementing those efforts, a team led by Barbara Czako, Ph.D., and Philip Jones, Ph.D., report the discovery of IACS-15414, a potent inhibitor of SHP2. In this preclinical study, IACS-15414 displayed an optimal pharmacokinetic profile in preclinical models as an oral therapy with no off-target effects. IACS-15414 also was effective at blocking activity of the MAPK signaling pathway and suppressing tumor growth in cancer models with activated receptor tyrosine kinase (RTK) signaling or mutant KRAS. Learn more in the Journal of Medicinal Chemistry.
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The University of Texas MD Anderson Cancer Center and the Rare Cancer Research Foundation today announced the launch of a collaboration designed to accelerate the development of new treatments for rare cancers by empowering all patients in the United States to contribute tumor samples directly to MD Anderson for translational research efforts.
This initiative is designed to overcome a major obstacle that has long prevented significant progress in rare cancer research — the lack of available samples. The Rare Cancer Research Foundation will use its Pattern.org online engagement platform to enable patients to donate tumor biopsies and surgical samples for research purposes.
With these samples, MD Anderson researchers will perform comprehensive analyses and will work to develop laboratory models that can be used to pursue new therapeutic strategies for rare cancers. New discoveries then can be used to design and launch clinical trials to evaluate these strategies for patients in need.
“The development of new rare cancer treatments is often stymied not by hard scientific questions but rather by the lack of patient models and datasets necessary to conduct research,” explained Mark Laabs, founder and chairman of the Rare Cancer Research Foundation. “We are delighted that this collaboration will empower patients nationwide to contribute their samples and medical information to cutting-edge work at MD Anderson and to accelerate the development of new treatments for rare cancers.”
Rare cancers are defined as those with fewer than 40,000 new cases diagnosed annually in the U.S. Taken together, rare cancers represent roughly 25% of all cancer cases and are the leading cause of cancer-related deaths. The Rare Cancer Research Foundation is committed to advancing research for these cancer types through strategic investments and innovative collaborations. MD Anderson is a world leader in the diagnosis and treatment of these cancers; more than 5,000 patients with the rarest diagnoses seek treatment at the institution each year.
“Our collaboration with the Rare Cancer Research Foundation allows rare cancer patients having surgery anywhere in the U.S. to join in the research effort by contributing excess tumor tissue, giving them the opportunity to truly make an impact on the entire community of these patients,” said Andy Futreal, Ph.D., chair of Genomic Medicine at MD Anderson. “Each piece of data or model generated is a potentially transformative tool that can advance our understanding and bring us closer to effective new therapies.”
MD Anderson established its Rare Tumor Initiative in 2019 to comprehensively characterize rare tumors throughout the course of each patients’ care. In 2021, the institution launched a translational research platform with the Broad Institute of MIT and Harvard, designed to create a catalog of rare cancer models and to provide a data resource for researchers in the field. The current collaboration will integrate with these efforts to further accelerate the pace of research and generate much-needed therapeutic insights.
Research efforts at MD Anderson will be led by Futreal and Timothy Heffernan, Ph.D., executive director of Translational Research to AdvanCe Therapeutics and Innovation in ONcology (TRACTION) platform. The work will focus on comprehensive molecular and functional characterization of donated tumor samples, with the potential to generate laboratory cell lines to enable further study. The initiative aims to fully characterize more than 60 rare cancer samples and develop 20 laboratory models. These data and models will be made available to the research community, allowing scientists worldwide to contribute breakthroughs to the field.