MD Anderson SPORE in Sarcoma

University of Texas MD Anderson Cancer Center

Principal Investigator:

Overview

Our overarching goal is to reduce sarcoma morbidity and mortality through innovative translational research focused on immunologic and targeted treatments. The program addresses two critical needs: (1) sarcomas are rare and complex, requiring a multidisciplinary, team-based approach, and (2) sarcomas span pediatric, adolescent-young adult, and adult populations, necessitating research that covers all age groups. The team includes clinicians, physician-scientists, statisticians, computational experts, and basic/translational scientists from eight departments across five MD Anderson divisions. The team is supported by patient advocates, external advisors, and administrative experts. Core resources include a Pathology and Tissue Core for molecular profiling and a Biostatistics and Bioinformatics Core for data analysis and risk stratification. Common research themes include targeting the immune system and tumor microenvironment, with a particular emphasis on osteosarcoma, where little progress has been made in over 30 years.

Research Projects:
•    Project 2: Develop adoptive cellular therapy for chordoma via clinical trial of T cells targeting Brachyury, a key chordoma protein.
•    Project 3: Evaluate and refine novel antibodies for osteosarcoma as antibody-drug conjugates in a phase 2 clinical trial

Project 2: Adoptive Cell Therapies for Chordomas

Project Co-Leaders: 

Cassian Yee, MD (Basic Co-Leader)
Anthony Conley, MD (Clinical Co-Leader) 

Specific Aims

Chordoma in its advanced stages is refractory to conventional therapy, creating an unmet need for effective treatments. Immune checkpoint therapy has produced only modest responses in this cancer, and adoptive cellular therapy (ACT) has been unavailable due to the absence of suitable immunogenic targets. Our proposal addresses these challenges by leveraging recent discoveries of highly immunogenic and novel antigens in chordoma, most notably Brachyury, a T-box transcription factor overexpressed in 95% of chordomas, and presented by common HLA alleles.

We propose the first-in-human phase IB clinical trial of ACT targeting Brachyury, using ETC (endogenous T cell) therapy—a cell therapy platform developed and refined in our laboratory over the past 15 years. ETC isolates and expands antigen-specific CD8 memory T cells from peripheral blood, generating more than 10 billion cells of uniform specificity and phenotype. Due to the durable central memory properties of ETC-derived T cells, lymphodepletion is not required prior to administration.

Building on this novel discovery of Brachyury-specific ETC cells and our clinical trial expertise, we plan to evaluate the safety, in vivo persistence, and anti-tumor efficacy of adoptively transferred ETC cells in patients with chordoma. The trial design allows for potential extension with additions such as immune checkpoint inhibitors (ICIs) or IL-7, given the favorable safety profile of ETC therapy.

To further enhance the therapeutic impact, we will also explore next-generation ETC therapy by engineering Brachyury-specific T cells with a proprietary stroma/collagen-disrupting IL-12 (attIL-12), developed in conjunction with collaborators at MD Anderson. Preclinical models suggest this approach may improve T cell infiltration and tumor killing.

Overall, this trial using Brachyury-targeting cell therapy aims to lay the foundation for subsequent combinatorial strategies and the continued development of innovative therapeutic approaches for patients with chordoma, addressing a critical gap in effective, targeted cancer therapy.

Project 3: Development of Novel Antibody Drug Conjugates for the Treatment of Osteosarcoma

Project Co-Leaders: 

Richard Gorlick, MD (Basic Co-Leader)
Andy Livingston, MD (Clinical Co-Leader)

Specific Aims

Pediatric osteosarcoma (OS) urgently requires new therapies since 30–40% of patients relapse after highly toxic chemotherapy, and no new treatments have been developed in over 30 years. Antibody-drug conjugates (ADCs), which deliver toxic payloads specifically to tumor cells while sparing normal tissue, are promising but remain unapproved for OS. Project 3 aims to develop and translate ADCs targeting surface proteins abundantly expressed in OS to improve treatment outcomes.

Preliminary data show that OS expresses accessible cell surface proteins suitable as therapeutic targets and epitopes for immunotherapy. Efficient clinical translation also depends on identifying biomarkers to select patients most likely to respond to treatment. Blood-based exosomes shed from tumors provide information on tumor evolution, metastasis, and relapse risk, and can guide patient selection.

The first aim focuses on ADCs targeting cell adhesion molecule 1 (CADM1), highly expressed in OS. Using patient-derived xenograft (PDX) models, we will optimize payloads, study resistance mechanisms, and prepare for IND filing. The second aim develops bispecific ADCs that combine two OS surface targets on a single antibody to enhance specificity and affinity. We propose combining CADM1 with B7-homologue 3 (B7H3), a known OS target, to improve efficacy.

The third aim will conduct a phase 1/2 trial of an established B7H3-targeting ADC in OS patients that assesses safety and preliminary efficacy. This trial also enables development of liquid biopsies using circulating exosomes to identify predictive treatment response signatures. Biospecimens will allow profiling of the OS surfaceome—proteins and modifications—to discover new targets and mechanisms of resistance.

This work is expected to provide effective, less toxic therapies for OS patients, addressing a critical unmet clinical need.

Administrative Core

Core Co-Directors: 

Richard Gorlick, MD 
Andrew Futreal, PhD

Specific Aims

The MD Anderson Sarcoma Specialized Program of Research Excellence (SPORE) Administrative Core (AC) will provide administrative and budgetary support to ensure the maximal success of the program. It will form the coordinating center for interactions within the MD Anderson SPORE community, as well as the community at large. The AC will be co-directed by Richard Gorlick, M.D., and Andrew Futreal, Ph.D., and supported by the SPORE Research Program Manager. The goals of the AC will be to provide coordination, oversight, and monitoring for the two Projects, the Biostatistics and Bioinformatics Core, and the Tissue and Pathology Core. In addition, it will coordinate the Developmental Research (DRP) and Career Enhancement (CEP) Programs. The overarching goals of the AC are to facilitate collaboration amongst Sarcoma SPORE investigators, institutional efforts, and external entities, including other SPORES and the NCI, as well as to coordinate Sarcoma SPORE clinical trial activities. The AC will support the activities of the Executive Committee, which is comprised of the Co-Directors, Project Co-Leaders, and Core Co-Directors.

Tissue and Pathology Core

Core Co-Directors: 

Alexander Lazar, MD, PhD
Wei-Lien Wang, MPH, MD

Specific Aims

The Tissue & Pathology Core coordinates the collection, processing, storage, and distribution of annotated human and murine biospecimens for all MD Anderson Sarcoma SPORE projects, including those from Developmental Research and Career Enhancement Programs. Co-led by two expert sarcoma pathologists, the Core collaborates with SPORE projects, institutional cores, and research labs to optimize fresh tissue collection and analyte extraction (DNA, RNA, protein) from both prospective and archival samples.

The Core supports molecular and immunological studies, including NanoString gene expression profiling, and distributes samples and analytes following strict operating procedures. The extensive institutional tissue bank includes over 4,000 snap-frozen sarcoma tumor samples and more than 8,500 formalin-fixed paraffin-embedded cases, with tissue microarrays covering 15+ sarcoma types.

Additional services include histologic characterization, immunohistochemistry, and interpretation for preclinical mouse model samples and serial human biopsies from clinical trials. Blood samples are processed for flow cytometry and exosome isolation. All biospecimen data and workflow details are managed within the Biospecimen Information Management System (BIMS™), ensuring comprehensive tracking and enabling successful translational sarcoma research.

Biostatistics and Bioinformatics Core

Core Director

Yisheng Li, PhD
Xiaoping Su, PhD

Specific Aims

The Biostatistics and Bioinformatics Core supports the MD Anderson Sarcoma SPORE’s mission to reduce sarcoma morbidity and mortality through translational research on immunologic and targeted therapies driven by genetic insights. This Core is a vital collaborative resource providing expert biostatistical and computational support for designing experiments, analyzing data, and advancing research methodology.

The Core assists all SPORE activities—including clinical trials, basic science projects, Developmental Research, and Career Enhancement programs—by guiding study design, statistical modeling, simulations, and data analysis to meet project aims. It generates detailed statistical reports, helps investigators publish findings, and ensures rigorous data sharing. Additionally, the Core develops innovative statistical and bioinformatics tools tailored to sarcoma translational studies. These include novel early phase adaptive clinical trial designs that incorporate mechanistic data such as pharmacokinetics and pharmacodynamics, and advanced methods for analyzing clinical trial data.

Overall, this Core enhances the scientific rigor and efficiency of sarcoma research at MD Anderson, enabling the integration of laboratory and clinical data to accelerate discovery and improve patient outcomes.  

Developmental Research Program

Program Co-Directors

Andrew Futreal, PhD
Shreyaskumar Patel, MD

Specific Aims

The purpose of the MD Anderson Sarcoma SPORE Developmental Research Program (DRP) is to identify and fund pilot research projects that have the potential to develop new methods to diagnose, treat, and monitor sarcomas, with the ultimate goal of reducing incidence and mortality and increasing survival rates of patients with sarcomas. The development of high-risk/high-reward projects is impossible without funds specifically allocated to encourage and develop such translational research projects. The Sarcoma SPORE DRP prioritizes the funding of high-risk/ high-reward translational clinical and laboratory-based projects that can lead to clinically testable hypotheses. The requirement of a “human endpoint” is waived for DRP projects; however, an overarching goal is to utilize DRP funds to collect the data necessary for proposing feasible “human endpoint” studies. DRP pilot projects may be collaborative among scientists within the Sarcoma SPORE and outside the SPORE community. Successful DRP projects may replace full Sarcoma SPORE projects that are not progressing as expected or those projects that have been completed successfully.

Career Enhancement Program

Program Director

Andrew Futreal, PhD

Specific Aims

The Career Enhancement Program (CEP) of this MD Anderson Sarcoma SPORE is designed to provide the necessary resources and support to encourage talented early career investigators to develop multidisciplinary skills to pursue and enhance translational sarcoma research careers. Sarcomas are relatively uncommon and encompass a broad group of cancers including bone and connective tissue cancers. By identifying, recruiting, and mentoring junior scientists and physician-scientists, we seek to enhance and increase translational research in sarcoma.