MD Anderson, Artios Pharma and ShangPharma announce in-licensing agreement for DNA damage response inhibitor
The University of Texas MD Anderson Cancer Center, Artios Pharma Limited and ShangPharma Innovation announced the in-licensing by Artios of a small-molecule ATR inhibitor program, developed jointly by MD Anderson and ShangPharma. The ATR inhibitor program is the result of an extensive collaboration between MD Anderson’s Therapeutics Discovery team and ShangPharma.
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.
Boehringer Ingelheim and The University of Texas MD Anderson Cancer Center today announced a new multi-year partnership to conduct collaborative research to rapidly advance therapies for various types of cancers, including gastrointestinal and lung cancers. The establishment of a joint Virtual Research and Development Center will enable effective data sharing and analysis between the organizations.
The partnership is built on a flexible framework, allowing for projects to enter at different stages (research, development and/or clinical stage) over several years. It further combines the unique patient-driven drug-development capabilities of MD Anderson’s Therapeutics Discovery division with the innovative pipeline of novel medicines from Boehringer Ingelheim.
MD Anderson’s Therapeutics Discovery division is a multidisciplinary team of clinicians and researchers focused on advancing the next generation of cancer therapies. As part of the division, the TRACTION (Translational Research to Advance Therapeutics and Innovation in Oncology) platform conducts cutting-edge translational research to better understand how new medicines work and which patients will see most benefit.
“We could not have chosen a better partner with all its research, translational and clinical expertise in lung and gastrointestinal cancers. Together, we hope to transform the treatment landscape for these diseases by tackling their root causes and drivers, that have so far remained elusive, exploring new and smart ways of killing cancer cells,” said Victoria Zazulina, M.D., corporate vice president and global head of Oncology, Medicine, at Boehringer Ingelheim. “Our innovative oncology pipeline coupled with strong partnerships like this will contribute to unravelling the complexities of these diseases and bringing innovative solutions to people with various types of cancers.”
The Virtual Research and Development Center will focus on the development of potential new treatments including:
- KRAS inhibition concepts, as mutations in the KRAS gene are common in various cancers, specifically in certain types of lung and gastrointestinal cancers.
- a TRAILR2 agonistic antibody, with the potential to selectively induce cancer cell death (apoptosis).
“Within MD Anderson, we are committed to a singular goal of ending cancer,” said Tim Heffernan, Ph.D., executive director of TRACTION at MD Anderson. “We look forward to working with Boehringer Ingelheim to advance their innovative pipeline of cancer medicines. Our Therapeutics Discovery team is well-poised to conduct impactful translational research, and this partnership will allow us to more rapidly advance much-needed new therapies to patients.”
More than 4.1 million people die from gastrointestinal and lung cancers every year worldwide, indicating an urgent need for new treatment approaches. Gastrointestinal cancers represent a heterogeneous complex array of diseases, and include oesophageal (throat), gastric (stomach), liver, pancreatic, and colorectal cancers. In 2018, lung cancer caused more than 1.7 million deaths. There are two main types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).
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.
Leukemia researchers at The University of Texas MD Anderson Cancer Center, working collaboratively with the Therapeutics Discovery division, have advanced a first-in-class therapeutic antibody into a Phase I clinical trial for patients with high-risk acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms.
The antibody, known as h8F4, is a T-cell receptor (TCR)-like antibody that can kill leukemia cells by targeting PR1, a peptide found selectively on the surface of leukemia cells.
The antibody originally was generated by the laboratory of Jeffrey Molldrem, M.D., professor of Stem Cell Transplantation & Cellular Therapy and chair ad interim of Hematopoietic Biology & Malignancy. Clinical production, testing and development was advanced by the Oncology Research for Biologics and Immunotherapy Translation (ORBIT) platform with support from an agreement with Astellas Pharma Inc.
New therapeutic options are needed for AML, explains Molldrem, to improve upon the standard chemotherapy leukemia treatment now available and bring lasting cures to more patients. While induction chemotherapy results in remission for roughly 70 percent of patients overall, many will experience relapse and just 25 percent will be alive 3-5 years later.
“The problem really is that you can’t eliminate the founder cells that initiate the leukemia process. They’re a rare population, and they’re hard to eliminate with standard therapy,” says Molldrem. “So we need something that has better outcomes, can help get rid of leukemia stem cells and is less toxic.”
PR1 peptide targeted for leukemia treatment
The PR1 peptide is normally found inside hematopoietic cells, the product of two protease enzymes. However, as Molldrem discovered, PR1 is selectively presented on the surface of leukemia cells by an immune-related protein called HLA-A2.
Recognizing the value of this as a leukemia target, researchers in Molldrem’s lab worked to develop h8F4, which binds PR1 in complex with HLA-A2 on the cell surface to induce death of the leukemia cells. In preclinical studies, h8F4 appeared to be effective at eliminating leukemia cells, particularly leukemia-initiating cells, in mouse xenograft models of human AML.
Based on preclinical data, ORBIT took responsibility for all aspects of drug development to advance h8F4 to the clinic. ORBIT completed all activities related to clinical drug chemistry, manufacturing and control, performed the necessary steps for Investigational New Drug (IND)-enabling studies, and completed safety, pharmacology and toxicology translational studies. The ORBIT team also developed assays for pharmacokinetics and immunogenicity.
Through their successful preclinical development and manufacturing work, the IND application was submitted and approved by the Food and Drug Administration. A Phase I clinical trial led by Jorge Cortes, M.D., professor of Leukemia, has opened and the first patient was treated in April.
The ORBIT platform is an integrated group of drug development experts working to advance novel monoclonal antibodies that target cancer cells or stimulate an immune response. As part of MD Anderson’s Therapeutics Discovery division, this team works collaboratively with MD Anderson clinicians and researchers to avoid traditional barriers to antibody development and bring new therapeutics from concept to clinic, all under one roof.
The platform is part of MD Anderson’s Moon Shots Program™, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.
“This is a great example of how a Moon Shots platform can work together with an MD Anderson clinician that has been working on this cancer biology for many years,” said Dongxing Zha, Ph.D., institute head, ORBIT platform. “We have a dedicated group that can complement our faculty’s skill sets and enable the development of these products. We are really proud of this kind of seamless collaboration to get this drug into the clinic.”
The development also would not have been possible without the support from Astellas. An option agreement signed in 2015 provided financial support for the clinical development and testing ORBIT completed before h8F4 could advance to the clinic. Sapna Parshottam, associate director of research planning & development in Molldrem’s group in Transplant Immunology, Stem Cell Transplantation and Cellular Therapy, was key in managing the alliance and facilitating each step of the regulatory and approval process for h8F4.
MD Anderson has implemented an Institutional Conflict of Interest Management and Monitoring Plan to protect patients and manage its financial conflict of interest regarding this research. You can read more here.
ORBIT and Molldrem’s lab now are collaborating to investigate alternative approaches to targeting PR1 in hematopoietic malignancies and other cancer types where it can be found. These include chimeric antigen receptor (CAR) approaches to target PR1 and overcome potential resistance to the h8F4 antibody.
Further, this approach broadens potential therapeutic targets by allowing researchers to go after proteins normally only found in the cell. Using the technology pioneered by Molldrem’s lab, the ORBIT platform now is working to expand their pipeline of therapeutic antibodies for targets abnormally presented on the surface of cancer cells, explains Zha.