The effectiveness of certain cancer treatments can often defy explanation, presenting a challenge in understanding the molecular drivers behind their success. This enigma is exemplified in the case of alveolar soft part sarcoma (ASPS), a rare cancer originating in the soft tissues of the torso or extremities that primarily affects children and young adults. ASPS emerges from a fusion event between ASPSCR1 (Alveolar Soft Part Sarcoma Chromosomal Region 1) on chromosome 17 and TFE3 (Transcription Factor E3) on the X chromosome, sparking the formation of tumors.
Despite its resistance to standard chemotherapy, ASPS responds remarkably well to checkpoint inhibitors, a form of immunotherapy. Curiously, ASPS exhibits none of the typical indicators that would predict a favorable response to immunotherapy. While these treatments can stave off progression for approximately two years, the disease inevitably advances over time, leading to fatal consequences.
Recognizing the imperative for a deeper understanding of the molecular intricacies of ASPS, Matthew Hemming, MD, PhD, along with his team, embarked on a mission. Armed with the knowledge that the fusion protein ASPCR1::TFE3 acts as a transcription factor, they employed state-of-the-art omics technologies to explore the epigenetic landscape of ASPS. Their recent findings, published in Cancer Research, have unveiled crucial insights essential for unraveling the molecular complexities of ASPS.
"We can leverage omics tools to pinpoint the genomic locations targeted by the fusion protein, observe acute changes in transcription and chromatin upon its degradation, and label it to track its interactions with other proteins," explains Dr. Hemming. Utilizing Chromatin Immunoprecipitation with Sequencing (ChIP-seq) and RNA sequencing, the team identified cyclin D1 as a highly expressed gene regulated by ASPCR1::TFE3. Cyclin D1 plays a pivotal role in cell cycle progression, forming a complex with the enzyme CDK4 to propel cells through the cell cycle.
The researchers made a significant breakthrough by demonstrating that Palbociclib, an FDA-approved inhibitor for breast cancer known to counteract CDK4/6, effectively inhibits the ASPCR1::TFE3 fusion protein. Their study successfully sets the stage for clinical trials by demonstrating efficacy across preclinical models, ASPS cell lines, and patient-derived xenografts—highly faithful in vivo models crafted by implanting patient tumors into immunodeficient mice. “We've identified basic foundational processes driven by the fusion protein, successfully demonstrating its vulnerability to the inhibitor, Palbociclib, and laid the groundwork for clinical trials," says Dr. Hemming. By disrupting the Cyclin D1/CDK4 complex, this drug induces cell cycle arrest in ASPS.
This research represents a significant leap forward in the pursuit of an effective treatment for ASPS. Deciphering the mechanistic underpinnings of ASPS and identifying avenues for therapeutic intervention offer hope for improved patient outcomes. While current immunotherapy for ASPS primarily targets extrinsic tumor features, such as the tumor microenvironment, Dr. Hemming's research has unearthed a cell-intrinsic vulnerability, enabling direct tumor targeting. With a lack of durable treatment options, there is an urgent need for novel therapies. Dr. Hemming’s study represents a successful stride in this direction. "With these findings, I can say to the clinical community, ‘Here's the science, here's our new understanding of this biology. Let's work together to collaboratively conduct a clinical trial.’"
