News

The University of Texas MD Anderson Cancer Center and Nexo Therapeutics today announced a multi-year strategic collaboration that aligns the innovative technology and capabilities of each organization at the earliest stages of drug discovery and development to rapidly advance impactful new cancer therapies against previously undruggable targets.

The agreement brings together Nexo’s unique drug discovery platform, which combines innovative covalent chemistry and chemical biology, with the translational research and drug development expertise of MD Anderson’s Translational Research to AdvanCe Therapeutics and Innovation in ONcology (TRACTION) platform. MD Anderson and Nexo will work together from discovery through investigational new drug-enabling studies to accelerate development of small-molecule therapies for patients with limited treatment options.

“We are excited to work with the team of researchers at MD Anderson to discover and develop novel cancer medicines targeting some of the fundamental drivers of cancer that have eluded past efforts,” said Andrew Phillips, Ph.D., founder and chief executive officer of Nexo Therapeutics. “By joining our complementary skills and capabilities at the earliest stages of drug discovery, we aim to enhance the prospects of rapidly advancing novel therapies to the clinic.”

Many promising cancer targets present significant hurdles for conventional drug development approaches based on the structure of the target as well as selectivity and pharmacological properties of the drug. The Nexo platform aims to systematically address each of these issues by combining a chemistry engine with chemical biology capabilities.

Nexo’s chemistry engine, CODON (Covalent Discovery and Optimization), combines a proprietary library that leverages chemical diversity and innovative covalent chemistries with scalable biochemical and in-cell proteomics. This allows the company to identify promising hit compounds and to conduct rapid optimization to produce compounds for in vivo studies.

The company’s unique chemical biology approach, INFINI-T (Informed Profile Before Initiation of Target), uses the power of chimeric fusion proteins to address target biology and pharmacology questions. The function of these chimeric proteins can be controlled by small molecules in cellular and in vivo models to generate detailed information about the required depth, duration and selectivity of target inhibition. Importantly, the INFINI-T platform provides target product profiles for medicinal chemistry well in advance of lead optimization. This is expected to decrease the time and capital needed to bring drug candidates to the clinic.

“Together with Nexo’s innovative platform, our integrated approach to translational research and drug development is poised to design and rapidly advance novel therapies against high priority oncology targets,” said Tim Heffernan, Ph.D., vice president of Oncology Research for TRACTION at MD Anderson. “This collaboration highlights our commitment to advancing innovative new medicines that address critical unmet needs for our patients.”

MD Anderson established the TRACTION platform to overcome traditional hurdles in oncology drug development and to quickly and safely advance the right treatments for the right patients. The platform incorporates a variety of cutting-edge technologies, disease modeling approaches and data analytics tools to better inform drug development, from discovery into clinical trials. The TRACTION platform 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 for cancer.

Beginning at the first stages of drug discovery and target identification, TRACTION researchers will collaborate with Nexo to characterize susceptible cancers, to identify potential combination treatment strategies and to evaluate biomarkers that can optimize patient selection.

Nexo and MD Anderson will collaborate on discovery and translation efforts, with the option to extend the collaboration into clinical development. Nexo will provide research support funding, and MD Anderson is eligible to receive certain royalties and payments based on a range of future development, regulatory, commercial and business milestones. Nexo will retain all rights to programs under the collaboration and will have sole responsibility for development, manufacturing and commercialization.

Disclosure

MD Anderson has an institutional conflict of interest with Nexo related to this research, and this relationship will be managed according to an MD Anderson Institutional Conflict of Interest Management and Monitoring Plan.

The University of Texas MD Anderson Cancer Center’s Research Highlights showcases the latest breakthroughs in cancer care, research and prevention. These advances are made possible through seamless collaboration between MD Anderson’s world-leading clinicians and scientists, bringing discoveries from the lab to the clinic and back.

Recent developments include results from a small-molecule inhibitor of oxidative phosphorylation, early antitumor response from a targeted therapy in patients with liposarcoma, the identification of epigenetic therapeutic targets in small cell lung cancer, a prognostic tool to help inform breast cancer therapy recommendations, a study of disparities in early mortality for adolescents and young adults with cancer, and a potential approach to improve treatment response in soft-tissue sarcomas.

Clinical trials of MD Anderson-developed therapy bring new insights to targeting oxidative phosphorylation
Certain tumors become dependent on the oxidative phosphorylation (OXPHOS) metabolic pathway for cellular energy production, making it an attractive target for new cancer therapies. However, clinical benefit with OXPHOS inhibitors has not yet been realized. Scientists in the Institute for Applied Cancer Science and the TRACTION platform, both part of MD Anderson’s Therapeutics Discovery division, developed the OXPHOS inhibitor IACS-10759, a small-molecule targeting the group of OXPHOS proteins known as Complex I. Timothy Yap, M.B.B.S., Ph.D., Naval Daver, M.D., Philip Jones, Ph.D., Joseph Marszalek, Ph.D., and colleagues evaluated IACS-10759 in two Phase I trials for advanced solid tumors and advanced acute myeloid leukemia. The treatment achieved transient target inhibition, but frequently was associated with neurotoxicity and elevated blood lactate levels. As a result, both trials were discontinued. The results reveal important insights for the field, providing guidance and caution for future development of OXPHOS inhibitors. Learn more in Nature Medicine.

MDM2 inhibitor milademetan shows early evidence of antitumor activity
The MDM2 protein is a negative regulator of the p53 tumor suppressor protein, and the MDM2 inhibitor milademetan aims to restore the p53’s antitumor activity. In a first-in-human Phase I trial led by David S. Hong, M.D., milademetan showed evidence of antitumor activity, especially in dedifferentiated liposarcoma. The primary objective in the study was to determine the recommended Phase II dose and schedule, which was found to be 260 mg once daily for three of 14 days. More continuous regimens were associated with on-target toxicities. In 107 patients, the overall disease control rate (DCR) was 45.8% and the median progression-free survival (PFS) was four months. In the subgroup with dedifferentiated liposarcomas, the DCR was 58.5% and median PFS was 7.2 months. The most common grade 3-4 drug-related adverse events were thrombocytopenia (29%), neutropenia (15%) and anemia (13.1%). Phase II and Phase III trials evaluating milademetan currently are underway. Learn more in the Journal of Clinical Oncology.

SET2,3 test added independent information to recurrence score for node-positive breast cancer
The 21-gene breast recurrence score (RS) is used to decide whether chemotherapy would provide additional benefit to hormone therapy alone for patients with lymph node-positive breast cancer. A different test (SET2,3 index) developed by Fraser Symmans, M.D., predicts the cancer’s sensitivity to endocrine therapy relative to baseline prognostic characteristics. Researchers from the National Clinical Trials Network’s Southwest Oncology Group (SWOG) tested whether the SET2,3 index added predictive or prognostic information to the RS using samples from the SWOG S8814 trial, which evaluated adjuvant anthracycline-based chemotherapy followed by tamoxifen hormone therapy for five years compared with tamoxifen alone. While SET2,3 index did not predict benefit from anthracycline-based chemotherapy, it had no correlation with RS and their combined results significantly improved prognostic assessment. Further work is needed to determine when and how multiple assays should be used in breast cancer treatment and to evaluate SET2,3 index with contemporary endocrine-based treatments. Read more in the Journal of Clinical Oncology.

Preclinical study identifies potential therapeutic targets in small cell lung cancer
Small cell lung cancer (SCLC) is highly malignant and has no currently approved targeted therapies. The CARM1 enzyme plays a role in promoting gene transcription, and its inhibition improves anti-tumor activity in various other cancers. However, its downstream targets are not well understood, and its therapeutic value has not been tested in SCLC. The NFIB transcription factor, which often is amplified in SCLC, is a substrate for CARM1. To characterize this relationship, researchers led by Guozhen Gao, Ph.D., Simone Hasumann, Ph.D., Pawel Mazur, Ph.D., and Mark Bedford, Ph.D., used in vivo SCLC models to show that CARM1 is a transcriptional coactivator for NFIB and affects gene expression through methylation at a single site. Losing NFIB methylation via CARM1 inhibition or NFIB mutation blocked tumor progression in these models. This study highlights NFIB amplification and CARM1 as drivers of rapid SCLC onset, meriting further investigation as therapeutic targets. Learn more in Nature Communications.

Disparities in early mortality persist for adolescent and young adults with cancer
While overall survival for adolescent and young adults (AYAs) with cancer has improved, with current five-year survival rates of more than 80%, a subset of patients remains at risk of dying shortly after their initial diagnosis, and certain sociodemographic factors have been associated with these disparities. To better understand these factors, researchers led by Michael Roth, M.D., used the Surveillance, Epidemiology, and End Results (SEER) database to analyze 268,501 AYAs diagnosed during a 16-year period. Results showed 3,854 AYAs died within two months of being diagnosed, and those with acute leukemia, liver, bile duct, pancreatic and lung cancer were at highest risk for early death. Hispanic and Black AYAs also were at the highest risk for early death, while other associated factors included lower socioeconomic status, limited or no health insurance, and presentation with higher stage disease at initial diagnosis. More research is needed to identify the underlying causes and reduce disparities in early survival for AYAs diagnosed with cancer. Learn more in the Journal of the National Cancer Institute.

Sequential targeting of cell cycle to prime retinoblastoma and induce DNA damage could improve anti-tumor response in sarcomas
Soft tissue sarcomas (STS) are rare cancers that form in tissues surrounding body organs, and there currently is a lack of effective treatment options. Reactivating the retinoblastoma (Rb) pathway with CDK4/6 inhibitors has been successful in other cancers, but these inhibitors have not shown much efficacy in STS as monotherapy or when combined with chemotherapy. Chemotherapy agents work by targeting a later stage of the cell cycle, making them inefficient if concurrent CDK4/6 inhibitors have already arrested cell cycle progression. Therefore, researchers led by Khandan Keyomarsi, Ph.D., evaluated a novel two-step sequential treatment approach. They first administered the CDK4/6 inhibitor abemaciclib to prime Rb-positive tumor cells, then removed the drug and allowed a recovery period, permitting the cell cycle to progress before giving chemotherapy. This sequential process, which can be non-invasively monitored in real time, effectively killed tumors in in vitro and in vivo, highlighting its therapeutic and clinical translation potential. Learn more in Cancer Research.

Recent awards and honors
Four MD Anderson researchers were elected members of the American Society for Clinical Investigation:

• Courtney DiNardo, M.D., associate professor of Leukemia
• Anirban Maitra, M.B.B.S., professor of Pathology and Translational Molecular Pathology
• Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation & Cellular Therapy
• Hussein Tawbi, M.D., Ph.D., professor of Melanoma Medical Oncology

In case you missed it
Read below to catch up on recent MD Anderson press releases.

• MD Anderson and Federation Bio announce collaboration to develop novel microbiome treatment for patients with immunotherapy-resistant cancers
• Three MD Anderson researchers elected AAAS Fellows
• Targeted therapy momelotinib provides significant symptom and anemia improvements in patients with myelofibrosis
• MD Anderson EGFR Classification licensed by BostonGene and Tempus to provide new insight on atypical mutations in lung cancer
• MD Anderson’s Jennifer Wargo receives TAMEST O’Donnell Award for pioneering microbiome research
• Scientists develop novel mRNA delivery method using extracellular vesicles