Dana-Farber Advances Novel Therapies for Adolescent and Young Adult Sarcomas
Key Insights
Dana-Farber's Adolescent and Young Adult Sarcoma (search) Program is running coordinated clinical trials spanning pediatric through adult age ranges for rare bone and soft tissue cancers.
Investigational approaches include LRRC15 (search)-targeted radioligand therapy for osteosarcoma (search) and B7H3 (search)-directed CAR T-cell therapy for sarcomas in patients ages 12 and older.
A STEAP1 (search)-targeting bispecific antibody is being evaluated in relapsed Ewing sarcoma (search), while a phase 1 trial of the RBM39 (search) degrader ST-01156 is open for patients over 18.
Sarcomas are rare and diverse cancers arising in bone or soft tissue, with more than 150 different variations. While treatment is advancing for some subtypes, most forms of the disease are still managed with chemotherapy, radiation, and/or surgery, and options remain limited when the cancer recurs. Dana-Farber Cancer Institute physician-scientists are now evaluating a portfolio of innovative therapies in clinical trials, with a particular focus on adolescent and young adult (AYA) patients—a group that has historically been underrepresented in sarcoma (search) clinical trials because it sits in a gray area between pediatric and adult oncology.
"We are uniquely positioned at Dana-Farber to run coordinated clinical trials across the age range from pediatrics through adulthood in sarcoma (search)," said pediatric oncologist David Shulman, MD, who leads the Adolescent and Young Adult Sarcoma Program at Dana-Farber. "We've demonstrated that we can successfully run trials for adolescents and young adults with sarcomas and we are excited to have a growing portfolio of drugs and clinical trials for these diseases."
Radioligand Therapy for Osteosarcoma
Osteosarcoma (search) is the most common bone tumor seen in children and young adults, with patients commonly diagnosed in their late teens. Standard treatment includes intensive, multi-agent chemotherapy and surgery, yet tumors recur in many patients. "Treatments really have not evolved for this disease since the 1980s," said Shulman.
Radioligand therapy (RLT), also called radiopharmaceutical therapy, is now being evaluated in a multicenter, industry-sponsored clinical trial for relapsed patients ages 12 and above. Shulman serves as one of the lead investigators. The therapy targets LRRC15 (search), a marker present on many sarcomas, and delivers radioactive particles into cancer cells expressing this marker. The approach requires close collaboration between sarcoma (search) specialists and nuclear medicine experts. "At Dana-Farber, we have highly trained staff to make sure that the radioactivity and these agents are given appropriately to patients and are administered in a safe manner," said Heather Jacene, MD, clinical director of Nuclear Medicine in the Department of Imaging. Dana-Farber is a Comprehensive Radiopharmaceutical Therapy Center of Excellence.
CAR T-Cell Therapy Targeting B7H3
CAR T-cell therapy has transformed the treatment of certain blood cancers, delivering lasting remissions and, in some cases, cures. Robbie Majzner, MD, a pediatric oncologist and researcher at Dana-Farber, is designing novel CAR T-cell therapies specifically for pediatric, adolescent, and young adult patients with cancer, including sarcomas.
A cell-surface marker called B7H3 (search), known to be present on many pediatric solid tumors, also occurs in several sarcomas. Antibody-drug conjugate (ADC) drugs targeting B7H3 have already been evaluated in clinical trials, and Majzner now plans to evaluate B7H3-targeting CAR T-cell therapy for AYA patients with sarcomas. "B7H3 is broadly expressed across sarcomas and at very high levels, making this an attractive target for B7H3 CAR T-cell therapy," said Majzner. A potential advantage of CAR T-cell therapy is that the trained T cells can persist for a long time in a patient after treatment, though the actual benefit must be confirmed in clinical trials.
STEAP1-Targeted Bispecific Antibody for Ewing Sarcoma
Ewing sarcoma (search) arises in bones or soft tissues and most commonly occurs in adolescents and young adults. Most patients who relapse after initial treatment do so within two years, and those who experience relapse have limited options. Approximately 90% of Ewing sarcoma tumors express a marker called STEAP1 (search). Agents targeting STEAP1 have recently shown activity in adult prostate cancer, results that drew the attention of Steven DuBois, MD, MS, director of Experimental Therapeutics in the Department of Pediatric Oncology.
DuBois is now evaluating a STEAP1 (search)-targeting bispecific antibody in AYA patients with relapsed Ewing sarcoma (search) who are age 12 and up. "Because of the structure of our program, we're able to deliver a clinical trial across that age spectrum," said DuBois. Bispecific T-cell engagers work by binding both immune cells (T cells) and cancer cells, bringing them together so the immune system can attack the cancer. "Some of the side effects of bispecific T-cell engagers can be similar to those of other cellular therapies," DuBois noted, adding that Dana-Farber/Boston Children's and Dana-Farber medical oncology have expertise in managing those side effects.
"Another Dana-Farber benefit is the cross-pollination of ideas across the entire spectrum of cancer care," said Suzanne George, MD, chief of the Division of Sarcoma (search) at Dana-Farber. "We have connections between pediatric oncology and adult oncology across the whole spectrum of diseases."
RBM39 Degrader ST-01156
Ewing sarcoma (search) is driven by a fusion protein—two proteins that bind together when they should not. Ewing sarcoma cells appear to be dependent on a protein called RBM39 (search), which is involved in the regulation of some cancer cells. This protein is difficult to block using traditional small molecule medicines, but a new approach employs targeted protein degradation to eliminate RBM39 from the cell and aims to control cancer cell growth.
At Dana-Farber, a phase 1 clinical trial of an RBM39 (search) degrader aims to determine whether the drug, currently code-named ST-01156, is safe and shows activity against Ewing sarcoma (search) and a range of other locally advanced or metastatic solid tumors. The degrader has shown significant activity against pre-clinical models of Ewing sarcoma. The trial is currently open for patients over 18. "ST-01156 aims to degrade RBM39 and therefore interfere with cellular function in Ewing sarcoma," said George, who is leading the study at Dana-Farber. "We're excited to learn more about this promising approach in Ewing and other sarcomas."
The Broader Challenge in Sarcoma Research
Sarcomas account for around 20% of all tumors in children and adolescents but only about 1% in adults, and several dozen different sarcoma (search) subtypes exist, complicating research. Targeted therapies and immunotherapies have transformed cancer medicine, particularly for common adult cancers, but most sarcomas—including those in children and young adults—have not been fightable to the same extent with these new therapies. This is because the tumors often find ways to evade the immune system or exhibit genetic mutations that are hard to treat in a targeted manner. Because sarcomas are rare diseases, the pharmaceutical industry has invested comparatively little in developing specific therapies, leaving medicine to rely mainly on surgery, chemotherapy, and radiation—treatments that can impair the quality of life of young patients long after therapy ends and that are not always effective, particularly if the cancer returns or spreads.