Removing a single protein may be enough to shut down a deadly soft-tissue cancer. In a new study from the University Of Texas Southwestern Medical Center, researchers show that mouse models of malignant peripheral nerve sheath tumor (MPNST) are completely eradicated when the growth factor BRD4 is inhibited. The findings add to the growing number of possible genetic targets for future cancer therapy.
Stopping a Tumor in its Tracks
Like that of many other types of aggressive cancer, the prognosis for MPNST is usually poor, as nerve clusters surrounding the tumor site make surgical intervention a next-to-impossible feat. Similarly, radiotherapy and chemotherapy is associated with limited results. The new study, which is published in the journal Cell Reports, sought to investigate new treatment strategies against the rare but deadly disease.
Instead of hunting new potential weak spots for conventional cytotoxic treatment, the authors decided to look into the biological machinery that drives the tumor growth itself. Why, they asked, does MPNST occur in the first place? To find out, they engineered a mouse model of the disease.
While watching the model tumors evolve towards their hosts’ demise, the researchers noticed something peculiar. The growth and survival of the cancers appeared to depend on a single bromodomain protein called BRD4 — a biomolecule involved in gene activation. In all models, this protein was expressed at unusually high levels, allowing another protein called BCL-2 to keep cancerous cells alive and well. When the researchers inhibited BRD4 by introducing an agent called JQ1, BCL-2 expression could not be sustained, and the tumor began to shrink.
"These treatments suppressed tumor growth and caused the cancer cells to undergo apoptosis, or cell death,” Lu Le, an assistant professor of dermatology and senior author of the study, said in a press release. “This is why BRD4 inhibition is exquisitely effective against MPNSTs and may represent a paradigm shift in therapy for these patients."
The current study exemplifies the emergence of new genetic targets for oncological therapy. Many experts argue that this type of inquiry represents the future of cancer research, as it reveals intervention techniques capable of reversing carcinogenesis altogether. A move toward these treatments would also reduce the incidence of the harrowing side effects currently associated with chemotherapy and radiotherapy.
A similar discovery recently lead to the development of ABT-199 — a breakthrough drug that combats leukemia by targeting the same protein that sustains MPNST growth. In a widely publicized Phase I study, the drug was shown to eliminate advanced chronic lymphocytic leukemia in 23 percent of the subjects. Developers hope that a finalized product will receive federal clearance for clinical use within the next three years.
Towards Improved Treatment Protocols For MPNST Patients
According to the National Institutes of Health (NIH). MPNST is a very rare cancer that occurs in about 0.001 percent of the population. It is considered aggressive, as it has a 65 percent chance of regrowing after clinical intervention. The five-year survival rate is about 50 percent — not great, in other words.
Right now, the authors of the current study are working with a pharmaceutical company to develop a BRD4-inhibiting drug for a clinical trial with MPNST patients. "This study identifies a potential new therapeutic target to combat MPNST, an incurable type of cancer that is typically fatal," Le told reporters. "The findings also provide important insight into what causes these tumors to develop."
Source: Patel A, Liao C, Chen Z, Liu C, Wang Y. “BET Bromodomain Inhibition Triggers Apoptosis of NF1-Associated Malignant Peripheral Nerve Sheath Tumors through Bim Induction.” Cell Reports. 2013.