Summary:

At the Case Comprehensive Cancer Center (Case CCC) in Cleveland, Ohio, the I’m Not Done Yet Foundation is supporting innovative sarcoma research focused on potential Adolescent and Young Adults (AYA) applications of existing cancer drugs currently only available to adults affected with Multiple Myeloma in clinical trials. This research, combined with promising developments in immunotherapy being spearheaded at the Case CCC under Dr. Alex Huang’s leadership, represents new hope for enhanced treatment of sarcomas in young people.

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The Case Comprehensive Cancer Center is a collaborative effort that combines the research prowess of Case Western Reserve University School of Medicine and the research and clinical expertise of its internationally renowned clinical affiliates, University Hospitals and Cleveland Clinic. 

 

The context:

Osteosarcoma (OS) is an aggressive malignant primary bone cancer with a high propensity for lung metastasis. OS frequently originates from primitive mesenchymal bone-forming cells in the long bones during periods of rapid bone growth. Consequently, OS represents the most prevalent bone cancers affecting children and adolescent and young adults (AYA), with ~400-600 cases a year and accounts roughly half of all new cases of OS diagnosed in the United States. Despite aggressive combination chemotherapy and surgery, the outcome for metastatic OS remains dismal, and the overall survival in children and AYA patients with metastatic OS has not improved significantly over the past 3 decades. A high proportion of OS patients develop metastatic disease at distant sites either at the time of diagnosis (one in five patients; 20%) or after initiation of multimodal therapy including combination chemotherapy and surgery (in ~30% of patients). The lung accounts for >80% of all OS metastatic sites. Unfortunately, almost all of the patients who develop surgically unresectable pulmonary metastatic OS invariably succumb to this devastating disease. Therefore, pOS represent a disease with urgent unmet needs.

 

The Science:

Led by Dr. Alex Huang, our multi-disciplinary investigator team at the Case Comprehensive Cancer Center and the Angie Fowler AYA Cancer Institute at UH Rainbow Babies & Children’s Hospital is determined to bring novel immune-based therapeutic options to pediatric and AYA patients suffering from this and other common aggressive sarcoma including Ewing Sarcoma and Rhabdomyosarcoma by providing concept-driving, novel “outside-of-the-box” and paradigm-shifting immunotherapeutic approaches.

 

With the support from the I’m Not Done Yet Foundation, we will propose to obtain pre-clinical data that would lend scientific support for the future development of a Phase I/II clinical trial targeting a common immuno-suppressive signaling pathway - the TGF / TGF Receptor pathway – within sarcoma microenvironment. It has been known for some time that TGF constitutes a dominant immune suppressive factor that is responsible for causing immune cell dysfunction. Therefore, effective pharmacologic inhibition of the TGF / TGF Receptor pathway has the potential to re-energize host immune system and allow for effective anti-tumor control of both primary and metastatic sarcomas. Recently, MedPacto, Inc.  developed a novel, orally available small molecule drug designed to directly target the TGF Receptor. Early Phase I trial in multiple myeloma at UH Seidman Cancer Center has shown safety, minimal toxicity and easily tolerability in adult patients. MedPacto has a strong desire to provide the drug (Vactosertib; TEW-7197) and sponsor a trial focused on AYA sarcoma if our group can demonstrate its efficacy in preclinical AYA sarcoma models.

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Given this unprecedented opportunity, we propose to test Vactosertib using a mouse OS model (K7M2). Within the next 12 months, we will test in vivo efficacy of Vactosertib for both primary bone tumors and metastatic lung lesions in the presence or absence of concomitant administration of other immunotherapeutic strategies, including anti-PD1 / anti-PDL1 immune checkpoint blocking antibodies, anti-CTLA4 immune checkpoint blocking antibodies, adoptively transferred ex vivo expanded Natural Killer (NK) cellular therapy, and liquid nitrogen-induced cryo-ablation therapy of metastatic lesions.

 

The Future:

Success of this preclinical pilot study will lead to the design of a Phase I/II clinical trial targeting OS, Ewing Sarcoma and Rhabdomyosarcoma in the AYA population. Data obtained from this pilot experiment will also be used to compete for additional funding from the NCI, St. Baldrick’s Foundation, Alex’s Lemonade Stand Foundation, Hyundai Hope-on-Wheels Foundation, Rally Foundation and other funding agencies.