Novel therapeutic antibody advances to AML clinical trials
The Therapeutics Discovery division and leukemia researchers 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 Therapeutics Discovery division at MD Anderson Cancer Center has advanced a new small-molecule inhibitor of cancer metabolism to Phase I clinical trials. This new drug candidate marks the fourth novel therapeutic brought from concept to clinical trial by Therapeutics Discovery, a drug-discovery engine built within the walls of MD Anderson to eliminate the bottlenecks that hamper traditional drug development.
The drug candidate, IPN60090, targets glutaminase (GLS1), an important enzyme for metabolic energy production in the cell. The small molecule, now being developed through a collaboration with the global biopharmaceutical company Ipsen Biopharmaceuticals, was first discovered and developed by researchers 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 Therapeutics Discovery.
The first-in-human Phase I clinical trial in patients with advanced solid tumors, led by Tim Yap, M.B.B.S., Ph.D., associate professor of Investigational Cancer Therapeutics and medical director of IACS, began in March by enrolling and treating its first patient.
“We are proud to see IPN60090 advance into clinical testing in partnership with Ipsen. This drug is the result of a significant collaborative effort to address unmet needs raised by our clinical colleagues, and it represents an innovative therapeutic opportunity for patients at MD Anderson,” says Phil Jones, Ph.D., vice president of Therapeutics Discovery and head of drug discovery for IACS.
Cancer treatment innovation
The IPN60090 program involves more than 25 Therapeutics Discovery team members across multiple platforms of oncology research. The IACS team, responsible for development of the small-molecule drug is led by medicinal chemist Mick Soth, Ph.D., institute group leader. The TRACTION team, which performed extensive translational biology work to clarify how the drug works and which patients are most likely to benefit, is led by biologist Jeffrey Kovacs, principal institute research scientist.
“Our unique approach to drug development, working with the bench at the bedside, affords us the opportunity to collaborate with MD Anderson physician-scientists, who helped guide our research and enabled us to rapidly advance this drug to the clinic,” saysTim Heffernan, Ph.D., executive director of TRACTION. “Now, through our partnership with Ipsen, we were able to further accelerate our efforts to investigate this drug in clinical trials and, hopefully, provide an effective new medicine for patients.”
Much of the development of IPN60090 was made possible through collaborative relationships with researchers in the Lung Cancer Moon Shot™ and Ovarian Cancer Moon Shot™, both part of MD Anderson’s Moon Shots Program™. The Moon Shots Program, which also supports the Therapeutics Discovery platforms, is a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.
MD Anderson and Ipsen announced their drug development partnership in 2018. Through the agreement, MD Anderson will progress IPN60090 through Phase I clinical development and Ipsen will be responsible for further global development and commercialization. MD Anderson and Ipsen also have collaborated to expand upon knowledge of the drug’s mechanism of action and possible expansion to additional indications. (MD Anderson has implemented an Institutional Conflict of Interest Management and Monitoring Plan to manage its financial conflict of interest regarding this research. You can read more here.)
In addition to IPN60090, Therapeutics Discovery has several other therapies now in clinical trials. The first small molecule was IACS-10759, which is now in Phase I trials for patients with acute myeloid leukemia and a variety of solid tumors. Two antibodies developed by the Oncology Research for Biologics and Immunotherapy Translation (ORBIT) platform also are now in clinical development.
“The robust pipeline and rapid development within Therapeutics Discovery speaks to the value of the group’s unique model of drug discovery”, says Jones. “We continue to strive each day to bring forward life-saving small-molecules, biologics and cellular therapies, inspired by the needs of our patients. This is our singular mission here – to improve the lives of those we treat at MD Anderson.”
A study at The University of Texas MD Anderson Cancer Center demonstrated how a small molecule drug discovered at the institution may help overcome resistance to treatment with ibrutinib in patients with mantle cell lymphoma.
The drug, IACS-10759, was the first therapy to be developed from concept to clinical trial by MD Anderson’s Therapeutics Discovery division, a unique drug-discovery engine created to answer unmet patient needs. IACS-10759 is currently in Phase I clinical trials for acute myeloid leukemia as well as for solid tumors and lymphoma.
Results from a study exploring the drug’s effectiveness in ibrutinib-resistant mantle cell lymphoma were published in the May 8 online issue of Science Translational Medicine.
The study explored the link between metabolic reprogramming and cancer cell growth, metastasis and therapeutic resistance, using three different patient-derived xenograft mouse models and genomic analysis of specimens. Metabolic reprogramming is an emerging hallmark of tumor biology in which cancer cells evolve to rely on two key metabolic processes – glycolysis and oxidative phosphorylation (OXPHOS) – to support their growth and survival.
“To investigate the therapeutic effects of IACS-10759, we developed an ibrutinib-resistant B-cell lymphoma mouse model using tumor cells isolated from cerebrospinal fluid from a patient who did not respond to multiple therapies including ibrutinib,” said Michael Wang, M.D., professor of Lymphoma & Myeloma and study lead. “We showed that metabolic reprogramming toward OXPHOS and glutaminolysis is associated with therapeutic resistance to ibrutinib in mantle cell lymphoma, an incurable B-cell lymphoma with poor clinical outcomes. Inhibition of OXPHOS with IACS-10759 results in marked growth inhibition in vivo and in vitro in ibrutinib-resistant, patient-derived cancer models.”
Clinical trials nationally have focused on the PI3K/AKT/mTOR pathway in relapsed and/or refractory lymphoma, but clinical success thus far has been limited. Wang’s team showed evidence that glutaminolysis and OXPHOS appear to be a prominent energy metabolism pathway in ibrutinib-resistant mantle cell lymphoma cells.
Ibrutinib was approved by the U.S. Food and Drug Administration in 2013 for treatment of relapsed/refractory mantle cell lymphoma and is now used as a front-line therapy. The drug has demonstrated anti-tumor activity with an overall response rate of 68 percent and median survival duration of 18 months.
Given that the one-year survival rate is 22 percent after relapse on ibrutinib, there is an urgent need to identify alternate therapeutic options for mantle cell lymphoma, according to co-senior author Linghua Wang, Ph.D., assistant professor of Genomic Medicine, who said the study “warrants the exploitation of active cancer metabolic pathways, especially OXPHOS and glutaminolysis, to improve clinical outcomes for mantle cell lymphoma and other lymphomas.”
Further investigation is ongoing and with a Phase I lymphoma trial that will include an ibrutinib-resistant cohort.
MD Anderson study team members included Liang Zhang, Ph.D.; Yixin Yao, Ph.D.; Yang Liu, Ph.D.; Hui Guo, Ph.D.; Makhdum Ahmed, M.D., Ph.D.; Taylor Bell; Hui Zhang; Elizabeth Lorence; Maria Badillo; and Krystle Nomie, Ph.D., all of the Department of Lymphoma & Myeloma; Shaojun Zhang, Ph.D.; Guangchun Han, Ph.D.; Xingzhi Song, Ph.D.; Jianjua Zhang, M.D., Ph.D.; Giulio Draetta, M.D., Ph.D.; and Andrew Futreal, Ph.D., of the Department of Genomic Medicine; Shouhao Zhou, Ph.D., of the Department of Biostatistics; Yuting Sun, Ph.D.; Emilia Di Francesco, Ph.D.; Tim Heffernan, Ph.D.; and Philip Jones, Ph.D., of the Institute for Applied Cancer Science and Center for Co-Clinical Trials; Lan Pham, Ph.D., of the Department of Hematopathology; and Philip Lorenzi, Ph.D., of the Department of Bioinformatics and Computational Biology. The Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences also participated in the study.
The study was funded by the National Institutes of Health (P30 CA016672, 1S10OD012304-01, and R21 CA202104); the Cancer Prevention and Research Institute of Texas (RP130397); T. Gary Rogers; the Kinder Foundation; the Cullen Foundation; the Leukemia and Lymphoma Society; and the Institute for Applied Cancer Science at MD Anderson. Wang reported no competing interests.
Researchers at The University of Texas MD Anderson Cancer Center have discovered that triple negative breast cancer (TNBC) cells can develop resistance to frontline, or neoadjuvant, chemotherapy not by acquiring permanent adaptations, but rather transiently turning on molecular pathways that protect the cells.
The study, published today in Science Translational Medicine, also identifies a vulnerability that may provide a new treatment option for resistant TNBC. Among those pathways activated is a metabolic process, known as oxidative phosphorylation, which can be targeted by a small-molecule drug developed by MD Anderson’s Therapeutics Discovery division.
“Modern chemotherapy is highly effective for nearly half of patients with triple negative breast cancers,” said corresponding author Helen Piwnica-Worms, Ph.D., professor of Experimental Radiation Oncology. “However, the remaining half of women will not fully respond to neoadjuvant chemotherapy, and there currently are no approved treatments to improve outcomes for them. Understanding how tumor cells become resistant will allow us to identify new targets to better treat resistant disease.”
According to the American Cancer Society, an estimated 268,000 women will be diagnosed with breast cancer this year, of which 15 to 20 percent will have TNBC. Standard treatment for patients with TNBC is neoadjuvant chemotherapy followed by surgery to remove the tumor. For women with tumors that don’t fully respond to chemotherapy, there is a much higher risk of recurrence and death from the disease, said Piwnica-Worms.
In order to study how TNBC cells become resistant to treatment, the researchers created mouse models, known as patient-derived xenografts (PDXs), of TNBC using tumor samples from patients enrolled in the ARTEMIS clinical trial, led by MD Anderson’s Breast Cancer Moon Shot™.
Patients enrolling in ARTEMIS have tumor biopsies taken before and after neoadjuvant chemotherapy treatment, which enable researchers to study why some tumors are resistant and discover more effective strategies to bring cures to more patients. The work 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.
Piwnica-Worms’ team identified several PDX models that responded to chemotherapy at first, but eventually developed resistance and resumed tumor growth. If treatment was paused, however, the residual tumors once again became sensitive to chemotherapy, indicating the resistance was temporary.
Under the microscope, tumors showed distinct changes during treatment, but regrown tumors appeared similar to those before treatment. Further, an analysis of individual tumor cells showed that the heterogeneity of cells in a given tumor was maintained after treatment, suggesting that chemotherapy did not select for a small subset of resistant cells.
Characterization of gene expression changes revealed a set of pathways activated as part of the resistant state, which were turned off when chemotherapy was discontinued. The researchers confirmed many of these molecular changes were mirrored in biopsies taken from ARTEMIS patients.
Hoping to find new treatment targets for resistant TNBC, the researchers discovered that these cells had become dependent on oxidative phosphorylation for energy production. This pathway is the target of IACS-10759, the first-small molecule drug discovered and developed by MD Anderson’s Therapeutics Discovery division.
When treating the PDX mice with IACS-10759 following chemotherapy treatment, the researchers observed a synergistic effect, suggesting sequential treatment of chemotherapy and IACS-10759 could prolong the duration of treatment response. IACS-10579 is now in clinical trials for a variety of hematological and solid cancer types.
“Our study provides a compelling rationale for defining additional properties that enable triple negative breast cancers to survive chemotherapy treatment, so that combination therapies can be developed to eradicate this disease,” says Piwnica-Worms. “A long-term goal is to avoid the use of chemotherapy in patients with resistant disease and instead employ targeted therapies to avoid unnecessary treatments and harsh side effects.”
The study was supported by the Cancer Prevention and Research Institute of Texas (RP150148 and RP160710, RP170668), the American Cancer Society, and the National Cancer Institute (CA016672). A full disclosure of conflicts of interest can be found here.
In addition to Piwnica-Worms, MD Anderson authors on the study include: Gloria Echeverria, Ph.D., Xiaomei Zhang, Ph.D., Sabrina Jeter-Jones, Xinhui Zhou, Shi-Rong Cai, M.D., Yizheng Tu, M.D., Ph.D., Aaron McCoy, and Jiansu Shao, M.D., all of Experimental Radiation Oncology; Zhongqi Ge, Ph.D., of Experimental Radiation Oncology and Bioinformatics and Computational Biology; Sahil Seth, of Genomic Medicine, of IACS and the TRACTION platform; Michael Peoples, Yuting Sun, Ph.D., Qing Chang, M.D., Christopher Bristow, Ph.D., Alessandro Carugo, Ph.D., XiaoYan Ma, M.D., Angela Harris, Vandhana Ramamoorthy, Joseph Marszalek, Ph.D., and Timothy Heffernan, Ph.D., all of IACS and the TRACTION platform; Yun Wu, M.D., Ph.D., and William Symmans, M.D., both of Pathology; and Stacy Moulder, M.D., of Breast Medical Oncology. Additional authors include Huan Qiu, of Integrative Biology and Pharmacology at The University of Texas Health Science Center, Houston, TX; and Jeffrey Chang, Ph.D., of Bioinformatics and Computational Biology at MD Anderson and Integrative Biology and Pharmacology at The University of Texas Health Science Center, Houston, TX.
"From the bench to the bedside" is a phrase often used to describe a drug discovery's journey from the laboratory to the clinic, where patients benefit.
MD Anderson's Therapeutics Discovery division, however, takes a different approach, by beginning with the bench at the bedside. This drug discovery engine conducts research informed by the clinic, from start to finish.
"We are completely driven by unmet needs we see in the patients that come to MD Anderson for help," says Phil Jones, Ph.D., vice president of Therapeutics Discovery. "Guided by the expertise of our world-class clinicians, our efforts begin with the patient and their cancer. The Therapeutics Discovery model is designed to develop new treatments to meet their needs."
Composed of three Moon Shots Program™ platforms and the Neurodegeneration Consortium, Therapeutics Discovery is working hard to bring transformational, life-saving medicines to patients quickly, safely and effectively. These medicines range from new chemical compounds to antibodies and cell-based therapies.
Unlike typical pharmaceutical companies, Therapeutics Discovery was built within the walls of MD Anderson, placing drug development expertise in unparalleled proximity to patients and leading physicians. It's a recipe for success that already is yielding promising results.
And at the heart of it all are more than 100 scientists, driven by a passion to see their work one day save a patient's life.
The Institute for Applied Cancer Science (IACS)
IACS is devoted to inventing new small-molecule drugs, or chemical compounds, that target specific vulnerabilities in cancer cells.
Principal research scientist Mick Soth, Ph.D., is a lead chemist for one of IACS’ drug discovery projects, and responsible for designing the safest and most effective compounds possible.
Soth spent more than a decade working for a major pharmaceutical company, but grew increasingly frustrated by limited successes and a lack of meaningful collaborations. He chose to join MD Anderson five years ago to find a new, more productive environment for drug development.
"I'm very excited about building something here," Soth says. "We're in a great spot to do drug discovery, with direct connections to MD Anderson clinicians, and we're building up what could become an operation that will elevate the institution, Houston and the state of Texas. That's really cool."
Soth already has two projects advancing to clinical trials early next year. That type of early success, coupled with tremendous cross-communication in the division, was exactly what he was looking for.
But what ultimately makes it all worthwhile?
"The first patient that is actually helped," Soth says.