New Hope for Childhood Cancers


University of Texas MD Anderson Cancer Center researchers have uncovered a vulnerability within malignant rhabdoid tumors (MRT), a rare pediatric cancer that lacks effective treatments.  The disease appears to be susceptible to medication that blocks the cancer cell’s ability to dispose of misfolded proteins.  This discovery may lead to new therapeutic agents targeting the SMARCB1 gene, which is the cause for MRT and other similar forms of malignancy.

It’s somewhat fortunate that these are very rare cancers.  With current treatments, the prognosis is ominous – just about one year,” explained co-author Giannicola Genovese, M.D.  “It’s an orphan disease, meaning it has no targeted treatments available.  The current options include high-dose chemotherapy, radiation, and surgery, which can cause significant developmental and neurological effects and increase the risk for secondary cancers later in life”.

The team used an embryonic mosaic approach which allowed them to circumvent many current limitations in technology and noticed that excess or misfolded proteins can be toxic to the cell.  In the absence of SMARCB1, the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress response pathways become hijacked and incorrectly activated to account for protein accumulation in malignant cells.

TP53 is the most frequently mutated gene in cancer, but it does not appear to be mutated in MRT.  We were excited to learn that, here, it’s functional because the cells need p53 to counterbalance the protein accumulation associated with SMARCB1 loss”, noted Alessandro Carugo, Ph.D., from the Institute for Applied Cancer Science (IACS).

With help from MD Anderson’s Therapeutics Discovery platforms, including IACS, the team developed a drug combination to target two important processes for clearing protein waste, autophagy and proteasome degradation.  Inhibiting these mechanisms resulted in complete tumor regression when applied to mouse models.  These findings were then confirmed with mouse transplants and cell lines derived from human MRT.

Now, researchers are testing a proteasome inhibitor in combination with chemotherapy for patients with renal medullary carcinoma (RMC), a rare form of kidney cancer which affects adolescents and young adults, also driven by SMARCB1 alterations.

This is the first trial designed specifically for SMARCB1-mutant RMC.  These are rare cancers that don’t respond to the standard of care for other kidney cancers”, said Genovese.  “There is a need for new therapies for treating these patients.  I think we’ve developed a good platform for discovery, to provide options for these patients and hope for the families as well”.

Scientists are determined to expand their research to include pediatric MRT and other SMARCB1-related cancers, hoping to provide assistance to many more cancer patients.