MD Anderson and Taiho Pharmaceutical announce collaboration to accelerate development of novel therapies for brain metastasis and other unmet medical needs
The University of Texas MD Anderson Cancer Center and Taiho Pharmaceutical Co., Ltd., announced a three-year strategic collaboration to accelerate the development of treatments for significant unmet medical needs in oncology, including patients with brain metastases and those with cancers refractory to available therapies.
New preclinical research from The University of Texas MD Anderson Cancer Center and BridgeBio Pharma, Inc. affiliate Navire Pharma, Inc., finds that the novel SHP2 inhibitor IACS-13909 is able to overcome multiple therapeutic-resistance mechanisms in non-small cell lung cancer (NSCLC), suggesting a possible new approach to treating cancers that have developed resistance to the targeted EGFR inhibitor osimertinib.
The data is published today in Cancer Research, a journal of the American Association for Cancer Research. IACS-13909 is a potent and selective allosteric SHP2 (Src homology 2 domain-containing phosphatase) inhibitor developed through collaboration between Navire and MD Anderson’s Therapeutics Discovery division. Based on these data, Navire plans to launch a clinical study of SHP2 inhibitors by the end of 2020 at multiple US sites, including MD Anderson.
IACS-13909 was initially discovered as an SHP2 inhibitor by a team of scientists in MD Anderson’s Institute for Applied Cancer Science (IACS) and Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platforms, both engines within the Therapeutics Discovery division.
“Tyrosine kinase inhibitors, like osimertinib, appear initially effective in suppressing tumor growth, but multiple mechanisms of resistance can develop while a patient is still receiving treatment,” said Nancy Kohl, Ph.D., a senior author of the study and member of Navire’s scientific advisory board. “This study shows that IACS-13909’s ability to inhibit a protein downstream of multiple signaling pathways is a promising approach in overcoming these common tumor-resistance mechanisms.”
Osimertinib is a targeted EGFR inhibitor used as a front-line option for treating patients with NSCLC harboring specific EGFR mutations. However, NSLCs frequently develop osimertinib resistance over time, either through additional mutations in EGFR that block activity of the drug, or by activating compensatory signaling pathways.
SHP2 is a protein that acts downstream in these pathways, and it is required for full activation of the MAPK signaling pathways, which is known to fuel tumor growth, proliferation and survival.
“Our findings show that IACS-13909 is capable of suppressing tumor cell proliferation in vitro and causing tumor regression in vivo for lung cancers harboring a variety of activated kinases as the oncogenic driver,” said lead author Yuting Sun, Ph.D., co-project lead and senior research scientist with TRACTION at MD Anderson. “These data suggest that targeting SHP2 could provide a viable strategy for overcoming osimertinib resistance occurring through a variety of mechanisms.”
These results were consistent when IACS-13909 was used as a single agent and in combination with osimertinib in vivo. The combination treatment in vitro led to prolonged, more durable responses in tumors that were sensitive to osimertinib and stimulated tumor regression in osimertinib-resistant models.
“Through our collaboration with the Therapeutics Discovery team at MD Anderson, we continue to uncover SHP2’s critical role in activating multiple different pathways related to cancer’s onset and growth,” said Eli Wallace, chief scientific officer of oncology at BridgeBio, Navire’s parent company. “This study further supports the very reason that Navire was founded – to develop novel SHP2 insights into targeted medicines for patients in need. We look forward to advancing our lead SHP2 inhibitor into the clinic later this year.”
The ongoing research is supported by Navire through a global licensing and development agreement, and the Therapeutics Discovery division is supported in part by MD Anderson’s Moon Shots Program®. MD Anderson has an institutional financial conflict of interest with Navire, and the research is managed according to MD Anderson’s Institutional Conflict of Interest Management and Monitoring Plan. A complete list of study co-authors and their disclosures can be found with the full paper here.
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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In a first-time disclosure of IPN60090, a small-molecule inhibitor of the metabolic enzyme glutaminase (GLS1), researchers from The University of Texas MD Anderson Cancer Center’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.
MD Anderson’s GLS1 program was initiated and advanced by a team of scientists in the Institute for Applied Cancer Science (IACS) and Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platforms, both engines within Therapeutics Discovery. Development of the program continues in collaboration with Ipsen, which licensed the therapeutic in 2018.
Findings and information about the ongoing trial will be presented today at the 2020 American Association for Cancer Research Virtual Annual Meeting I by Jeffrey Kovacs, Ph.D., institute group leader with TRACTION and co-leader of the GLS1 program.
“This effort is a great example of our strategy within Therapeutics Discovery, taking a comprehensive approach to personalized medicine,” said Kovacs. “Our preclinical data suggest that IPN60090 may be effective in underserved groups of patients who need better treatment options, and we look forward to results from our ongoing clinical trials.”
Dysregulation of cellular metabolism is a hallmark of cancer development, and the GLS1 enzyme plays a key role in many metabolic processes. Thus, it makes an attractive target for cancer therapy, explained Kovacs.
IACS drug-discovery scientists identified IPN60090 as a potent and selective inhibitor of GLS1 suitable for clinical trials, and translational researchers in TRACTION demonstrated its activity against subsets of lung and ovarian cancer preclinical models.
Further analysis revealed biomarkers of response, which have been leveraged to identify patients most likely to benefit. In lung cancers, mutations in the KEAP1 and NFE2L2 genes, which regulate response to oxidative stress, sensitize cells to treatment with IPN60090. Similarly, low expression of the metabolic protein asparagine synthetase (ASNS) in ovarian cancers predicts response to IPN60090 in preclinical models.
“Identifying these putative predictive biomarkers of response is critical for our ongoing clinical efforts to ensure that we’re able to offer patients the most relevant therapies,” said Timothy A. Yap, M.B.B.S., Ph.D., F.R.C.P., associate professor of Investigational Cancer Therapeutics and medical director of IACS. “These patient groups in particular, which represent distinct niches within those cancer types, are in need of more effective treatment options.”
For example, patients with lung cancers harboring KEAP1/NRF2 mutations have not benefited from treatment with immune checkpoint inhibitors and have poorer outcomes overall, explained Yap, who leads the IPN60090 clinical trial at MD Anderson.
IPN60090 currently is under investigation in a Phase I dose-escalation and dose-expansion study for patients with advanced solid tumors that harbor KEAP1/NFE2L2 mutations or have low ASNS levels. The team has developed novel CLIA-certified assays to identify patients likely to benefit and monitor how effectively the drug is acting. Initial data from the clinical trial indicate that IPN60090 is effectively inhibiting GLS1 activity in peripheral blood mononuclear cells from patients.
Future trial cohorts plan to investigate IPN60090 in combination with checkpoint inhibitors, chemotherapy and targeted therapies identified by the researchers as having potential synergistic benefits with GLS1 inhibition.
The ongoing research is supported by Ipsen through a global licensing and development agreement. The research is managed according to MD Anderson’s Institutional Conflict of Interest Management and Monitoring Plan. Kovacs is a co-inventor on material and method-of-use patent applications related to IPN60090. The Therapeutics Discovery division is supported in part by MD Anderson’s Moon Shots Program.
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.”