MD Anderson, Ipsen advance new therapy with potential benefit for underserved lung and ovarian cancer patients
In a first-time disclosure of IPN60090, a small-molecule inhibitor of the metabolic enzyme glutaminase (GLS1), researchers from MD Anderson's Therapeutics Discovery division and Ipsen Biopharmaceuticals reported the preclinical discovery and early-stage clinical development of this novel drug. IPN60090, now under investigation in a Phase I trial, may hold benefit for certain patients with lung and ovarian cancers.
Cellular therapies have emerged as an effective new therapy for patients with certain types of cancer, and MD Anderson has played an important role in advancing these novel treatments to the clinic. With recent agreements, MD Anderson has expanded its manufacturing and research capacity for cell therapies to bring new treatment options to more patients.
This month, MD Anderson finalized an asset purchase agreement with Bellicum Pharmaceuticals, Inc., to acquire its 60,000 sq. ft. cellular therapy manufacturing facility in the Texas Medical Center for $15 million. MD Anderson will operate this facility for its own internal programs and strategic partners.
Agreement offers new promise for cellular therapies
This manufacturing facility provides industrial capacity and expertise to accelerate MD Anderson’s cellular therapy efforts toward meaningful clinical advances, explains Jason Bock, Ph.D., vice president of Therapeutics Discovery and head of Biologics Product Development.
“We are excited to leverage this state-of-the-art development and
GMP manufacturing facility to dramatically accelerate
MD Anderson’s cell therapy programs,” says Bock.
The Therapeutics Discovery division is a unique drug discovery and development engine within MD Anderson, created to advance the next generation of impactful cancer medicines. This team of more than 100 researchers, clinicians and drug-development experts work with unmatched clinical insight to develop new therapies, including small molecules, biologics and cellular therapies, to answer unmet medical needs in oncology.
January is National Biotechnology Month, which recognizes the potential of biotechnology innovations to improve the lives of Americans. MD Anderson’s commitment to research, innovation and drug discovery is aligned with this goal and our mission to end cancer.
The Therapeutics Discovery team also works closely with
MD Anderson’s adoptive cell therapy (ACT) platform, which is working to create a variety of novel cellular therapy approaches for treating cancer. The ACT and Therapeutics Discovery platforms are part of the institution’s Moon Shots Program®, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.
Bringing cutting-edge natural killer cell and T cell therapies to the clinic
With the support of the Moon Shots Program and ACT platform, Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation and Cellular Therapy, developed MD Anderson’s chimeric antigen receptor (CAR)-modified natural killer (NK) cell therapy platform.
In November 2019, MD Anderson announced an exclusive license agreement and research agreement with Takeda Pharmaceutical Company to develop four CAR NK therapies. With continued support from the ACT platform and Therapeutics Discovery teams, MD Anderson will work with Takeda to bring the lead CAR NK therapy into pivotal clinical trials in 2021.
The ACT platform also is working to advance endogenous T-cell therapy, pioneered by platform co-leader Cassian Yee, M.D., professor of Melanoma Medical Oncology. This work has initiated several early-phase clinical trials as well as the launch of Immatics US, Inc., which is focused on developing a variety of T-cell therapies.
Additionally, Sattva Neelapu, M.D., and Michael Wang, M.D., both professors of Lymphoma & Myeloma, lead pivotal trials investigating the use of CD19 CAR T cells for treating large B cell lymphoma and mantle cell lymphoma, respectively, demonstrating the clinical expertise in novel cell therapies within MD Anderson.
“By synergizing the cell therapy research platforms and depth of clinical development experience with our newly acquired industrial capabilities, MD Anderson has created an unrivaled end-to-end engine to bring the most cutting-edge therapeutics from the lab to patients who need them,” says Bock.
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Despite major recent advances in oncology drug discovery, including the development of innovative targeted, immune and cell-based therapies, there remain many opportunities to improve outcomes for patients with cancer. Some may not benefit from available treatments, and others may have highly aggressive or drug-resistant cancers that require new options.
As part of MD Anderson’s commitment to bring our patients the most effective, safest treatments possible, MD Anderson established the TRACTION platform - a state-of-the-art translational biology engine to address the challenges of drug discovery by enabling highly innovative, collaborative oncology research.
TRACTION - Translational Research to AdvanCe Therapeutics and Innovation in Oncology - is a core component of MD Anderson’s Therapeutics Discovery Division, a unique group of clinicians, researchers and drug discovery scientists working to develop innovative cancer treatment options, inspired by the needs of patients and guided by the expertise of MD Anderson physicians.
TRACTION is one of the research platforms launched by MD Anderson’s Moon Shots Program® to provide unique expertise, technical support and novel infrastructure to enable impactful research projects. The Moon Shots Program is a collaborative effort to rapidly develop scientific discoveries into meaningful clinical advances that save patients’ lives.
Tim Heffernan, Ph.D., executive director of TRACTION, spoke with Cancer Frontline about the platform and how it is contributing to MD Anderson’s goal of Making Cancer History.
Q: Can you briefly describe the work of the TRACTION platform?
A: TRACTION functions as an industrialized translational research platform with the overarching goal of accelerating the translation of new knowledge into clinical impact.
Our work covers a few major themes that aim to address several challenges we face in oncology drug discovery and development - namely new targets, new mechanisms, new drugs and better predictive platforms. We take a comprehensive approach that includes:
· Deploying disruptive technologies to identify and evaluate novel tumor dependencies
· Performing fundamental mechanistic biology to explore new therapeutic or target hypotheses
· Leveraging patient-centric translational platforms to identify which patients will most likely benefit from a given therapy.
Through our investment in patient-centric research, we have developed the infrastructure, platforms and capabilities to enable collaborative translational research. By partnering with the drug discovery engines within Therapeutics Discovery, we aim to advance a portfolio of new medicines for our patients.
Q: How is the TRACTION platform organized to carry out this work?
We’re organized into cross-functional units that guide our research and development. Our “Discovery and Innovation” group employs technology platforms and advanced data analytics to evaluate new therapeutic concepts that fuel our early stage drug discovery pipeline. This group evaluates trends emerging from clinical data and seeks to understand the fundamental biological mechanisms of drug response, tumor heterogeneity and tumor evolution to uncover novel therapeutic concepts.
Our “Target Biology” group executes mechanistic studies on specific targets to advance our internal drug discovery and development portfolio from concept to IND filing. These studies inform on target biology, adaptive responses and mechanistic co-extinction, ultimately allowing us to formulate definitive hypotheses to guide clinical development.
Lastly, our “Translational Biology” team supports drug development by providing industry-scale disease modeling, translational biology, in vivo pharmacology and biomarker development capabilities. Through integration with disease site experts, this team curates a comprehensive, patient-centric toolbox of preclinical models for studies that guide clinical development and identify appropriate biomarkers of response.
Q: TRACTION is a new name for the platform. How does this name better reflect your goals and scope of work?
A: Our rebranding from the Center for Co-Clinical Trials to TRACTION more accurately reflects our comprehensive approach to support research-driven patient care. Early on, we had established a number of translational partnerships with Moon Shots disease sites, and we soon realized the opportunity to expand our efforts into early discovery by leveraging our unique access to clinical and research data.
Thus, we expanded our group, enhanced our capabilities and fostered partnerships with other enabling platforms, such as APOLLO and TRA. Through these partnerships, we can better deploy our resources and capabilities to uncover novel concepts that could eventually uncover new clinical hypotheses and/or feed our Therapeutics Discovery pipeline. Our expansion has fostered collaborations across the institution to explore novel concepts in rare cancers, early disease, drug resistance, tumor evolution and immuno-oncology.
Q: How is your patient-driven translational approach unique from other companies or groups working in this area?
A: The fundamental differences are access, integration and scientific engagement. There are many organizations performing translational research, but at MD Anderson, we benefit from the fact that research begins and ends with the patient.
Within TRACTION, we implement reverse translation through unique and unprecedented access to clinical samples, profiling data and treatment outcomes to prioritize our next experimental question. Integration across MDA is essential as our programs are enabled through symbiotic relationships that we have developed across basic-, clinical- and applied-research disciplines, where we benefit from the expertise across MD Anderson to drive innovation around programs with the greatest probability of catalyzing transformative advances.
A third level of differentiation is scientific engagement. We are not a core facility nor a fee-for-service organization. Rather, the collaborations that we establish are true partnerships where we ensure that all parties involved are committed to maximize the clinical impact of new therapeutics.
Q: You recently announced a strategic partnership with Boehringer Ingelheim. Can you discuss how corporate partnerships contribute to your mission?
A: Corporate partnerships are essential to our mission. We work closely with our colleagues within Strategic Industry Ventures to identify potential partners and facilitate a discussion focused on a clinically translatable research plan.
Our decision to partner is based on several factors. Most importantly, we look for alignment with an area of strength within TRACTION and MD Anderson. We’re most interested in partnerships that could complement our internal portfolio within Therapeutics Discovery, and most importantly, have the potential to provide MD Anderson patients with new therapeutic options.
In addition to our patient-centric translational platforms, our ability to engage research and clinical faculty throughout the lifespan of a project are key factors that differentiate us from other translational organizations. Our partners value that, through integration, we bridge the gap between preclinical discovery and clinical development by providing a direct line of sight to the clinic.
Q: How has your team collaborated across the institution to achieve significant patient impact?
A: TRACTION supports the mission of MD Anderson by providing infrastructure, capabilities, and resources to evaluate translational hypotheses generated by investigators across the institution. Over the last six years, we have collaborated with multiple Moon Shots to generate preclinical data that have informed the design of several clinical trials, including novel and repurposed drugs as single-agent and combination therapies.
We have built on these collaborations to establish a number of exciting efforts ongoing with various Moon Shots teams. These programs span the drug discovery and development continuum, from target discovery through preclinical evaluation of new therapeutics. Indeed, Moon Shots collaborations have been critical in our success to advance therapeutic concepts within our own Therapeutics Discovery Division, most notably, IACS-10759 and IPN-60090, two clinical programs advanced in partnership with the Institute for Applied Cancer Science.
I would emphasize that our collaborative efforts are not limited to Moon Shots programs. We have established relationships across the institution in support of highly innovative science aimed at addressing unmet clinical needs. In line with our expanded scope and reach, TRACTION has recently deployed resources to support two important MD Anderson initiatives.
In partnership with Andy Futreal, Ph.D., and Ignacio Wistuba, M.D., co-leaders of the APOLLO platform, we are providing support to discover and develop new therapeutic concepts emerging from the Rare Tumor Initiative. A second area of interest, in collaboration with Hussein Tawbi, M.D., Jing Li, M.D., Ganesh Rao, M.D., and Michael Davies, M.D., Ph.D., focuses on enhancing our understanding of the biology of brain metastases to identify novel strategies that could be advanced in the new MD Anderson Brain Metastasis Clinic. Both of these initiatives rely on multidisciplinary teams that represent unique areas of strength at MD Anderson.
With the support of the Moon Shots Program and its investment in team science, together with the tremendous collaboration we see across MD Anderson, we aim to accelerate the pace of discovery. We already have helped advance several therapies into clinical trials, and we will continue to execute a multidisciplinary approach to overcome the traditional challenges in cancer drug discovery – all to bring new therapies to our patients that need them most.
The University of Texas MD Anderson Cancer Center, Artios Pharma Limited and ShangPharma Innovation today announce the in-licensing by Artios of a small-molecule ATR inhibitor program, developed jointly by MD Anderson and ShangPharma.
Under the agreement, Artios has exclusive rights to research, develop, manufacture and commercialize products globally. The lead candidate is expected to be ready for Investigational New Drug (IND) application by the second half of 2020.
“This program has the potential to be a highly effective DNA damage response (DDR) targeted treatment in cancer. We look forward to advancing the work done by MD Anderson and ShangPharma for the benefit of cancer patients,” said Dr. Niall Martin, chief executive officer at Artios Pharma. “The addition of the ATR programe further supports our position as a leader in the DDR space and strengthens our growing portfolio of assets, which includes a leading Polθ program, currently in candidate IND evaluation, and a large discovery stage platform of novel DNA repair nuclease inhibitors.”
The ATR inhibitor program is the result of an extensive collaboration between MD Anderson’s Therapeutics Discovery team and ShangPharma. Therapeutics Discovery is a multidisciplinary team created within MD Anderson to advance the next generation of cancer therapies to answer unmet oncology needs.
“Targeting DNA damage repair has the potential to provide an important therapeutic option for many patients in need of new treatments,” said Philip Jones, Ph.D., vice president of Therapeutics Discovery at MD Anderson. “We are pleased Artios will leverage its unique expertise in this field to advance this novel therapy toward the clinic to improve outcomes for cancer patients.”
ATR is an important signalling protein in DNA double strand break repair and replication stress. Through inhibition of ATR, tumors bearing an ATM deficiency can be selectively killed through a concept known as synthetic lethality. High levels of ATM mutations and protein loss have been characterised across many different tumor types, creating a significant opportunity for ATR inhibitors clinically. Based on clinical observations at MD Anderson, Therapeutics Discovery engaged with ShangPharma and its affiliate, ChemPartner, to develop small-molecule inhibitors of the DDR that could benefit patients across multiple cancer types.
“We are proud of the entire collaboration team, including ChemPartner, led by Sarah Lively, Ph.D., vice president of Innovation and New Technologies, for advancing the programe from early-stage research to formal drug discovery and development,” said Walter Moos, Ph.D., chief executive officer of ShangPharma. “We are pleased to transition this important program to the capable development team at Artios, and we hope this ultimately provides an impactful therapy for those afflicted with cancer.”
Repurposing FDA-approved therapies is a cost-effective way to bring new treatments to patients in need, but identifying those drugs with benefits in new indications can be a challenging discovery process.
A team of researchers led by MD Anderson and the IRCCS Regina Elena National Cancer Institute in Rome have used a novel computer-aided drug discovery approach to identify decitabine, an FDA approved therapy for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as a candidate for treating pancreatic cancers driven by mutations in the KRAS gene.
Pancreatic cancer is among the most lethal cancer types, with a five-year survival rate under 10%, due in part to a lack of effective therapies. Nearly all pancreatic cancers have a mutation in the KRAS gene, which leads to the activation of gene pathways that spur tumor growth. Unfortunately, despite broad efforts in the field, an effective KRAS inhibitor has yet to reach the clinic.
“One of the faster ways to discover new therapies is through precise repositioning of approved, safe therapies in novel indications,” says co-corresponding author Alessandro Carugo, Ph.D., Functional Genomics and Innovation Biology Group leader with MD Anderson’s TRACTION platform. “With this in mind, we leveraged a sophisticated approach of network pharmacology to identify approved therapies that could act as inhibitors of oncogenic KRAS.”
Algorithm points to decitabine for pancreatic cancer treatment
The researchers used an algorithm designed to analyze gene expression changes in response to drug treatment. By inputting a gene signature specific to KRAS-driven cancers, they identified drugs that could reverse those gene expression changes, thereby acting as KRAS inhibitors. This approach pointed to decitabine (5-aza-2'-deoxycytidine) as the top candidate.
Decitabine is an analogue of the nucleotide cytidine, a normal component of DNA. Upon treatment, decitabine is incorporated into DNA and disrupts essential chemical modifications, known as methylation, to the DNA backbone. This loss of methylation leads to the activation of previously silenced genome regions and increased gene expression.
To validate decitabine in this setting, the team utilized the translational biology capabilities of MD Anderson’s TRACTION platform, part of the institution’s Therapeutics Discovery division. This unique drug discovery and development engine within MD Anderson is advancing the next generation of cancer medicines from concept to clinical trial, all under one roof.
In cancer cell lines and mouse models of patient tumors, decitabine blocked cell proliferation, slowed tumor growth and reduced metastatic spread of the tumor. However, this effect was not ubiquitous for all pancreatic cancer models with KRAS mutations, but only those cancers dependent on oncogenic KRAS.
“By exploiting the immense translational resources of the Therapeutics Discovery platforms, we were able to develop a refined signature to predictively stratify patients based on KRAS dependency, so that we can better position decitabine for pancreatic cancer patients most likely to benefit,” says Carugo.
Based on this signature, the authors estimate that 30-50% of patients with pancreatic cancer have KRAS-dependent tumors. Going forward, the researchers suggested these results warrant evaluation in clinical trials to determine if decitabine can provide clinical benefit to this patient population.
Additionally, there may be opportunities to evaluate this approach in alternative cancer types commonly driven by KRAS mutations, such as lung and colorectal cancers. Work is ongoing to explore the response to decitabine in models of those diseases.
This study was supported with funding from the AACR Pancreatic Cancer Action Network and the Sewell Family Chair in Genomic Medicine. The Therapeutics Discovery platforms are supported by MD Anderson’s Moon Shots Program®, a collaborative effort to advance scientific discoveries into clinical advances that save patients’ lives.