Has the Tasmanian Devil Revealed a New Mechanism to Induce Regression of NF1 Tumors?
Abstract
Spontaneous cancer regression is a very rare event that has intrigued physicians and patients for centuries. In the 20th century, medical and scientific communities often dismissed such cases as anecdotal and of little value to the design of patient care. More recently, this early work on cancer regression recognizes these studies as the beginnings of the very exciting fields of cancer immunology and immunotherapy. Despite this revaluation, spontaneous cancer regression is very difficult to study for several reasons. First, it is estimated to occur at only about 1 in 60,000 human cases. Second, spontaneous cancer regression is defined as that which occurs in the absence of any treatment that could plausibly contribute to a positive response. In cancers such as the malignant peripheral nerve sheath tumors (MPNSTs) that cause significant mortality in NF1 patients, current treatment options of surgery, chemotherapy and radiation produce some patient benefits even though they are not usually curative. Thus, it would not be ethical to design a study in which material is collected for study, no treatment is given, and then later it is hoped that regressed material would be available to define how any rare spontaneous regression occurred. Tasmanian devils are the apex predator on the island of Tasmania, Australia. In 1996, a new and rapidly fatal disease was described in the wild population that caused a sharp decrease in numbers and forecasts that the species would be extinct within 50 years. The malady is characterized by large tumors that grow on the face of the animals (hence devil facial tumor disease, or DFTD) with local tissue invasion and, in the majority of cases, metastasis to distant organs. In addition to the spread within the animal itself, DFTD is transmitted through the population through biting behaviors that directly transfer cancer cells to a new host. Thus, a malignant cancer, which would normally be limited by the lifetime of the originating host, has escaped that restriction to become a plague upon the entire population. Most animal diseases receive little investigation unless occurring in agriculturally important or companion species. DFTD is an exception due to its extremely unusual characteristics and potential for immense ecological damage through the predicted extinction event. Tour-de-force research by (1) trapping animals to sample their cancers and install tracking, (2) releasing back into the wild, and (3) later retrapping to record disease progression/stability/regression and resample their cancers has revealed that: 1. DFTD cancers are MPNSTs that arise from Schwann cells, i.e., DFTD cancers have a similar cell of origin as NF1 nerve sheath tumors. 2. Spontaneous regression occurred in fewer than 20 cases from 10,000 affected animals. 3. Spontaneous regression was driven by a single point mutation that turned on a gene called RASL11A. 4. DFTD cancers that lack RASL11A did not regress and continued to kill the animals 5. Expression of RASL11A in cells derived from non-regressed DFTD cancers was sufficient to reduce their proliferation in a cell culture model. We recently completed a small pilot study of gene expression in human cutaneous neurofibroma (cNF) samples from NF1 patients in comparison to Schwann cells with normal neurofibromin expression. One striking result was the loss of RASL11A expression in all of the cNF samples tested. This is a novel finding for the NF1 field: there are no published reports linking RASL11A and NF1. Our long-term goal is to define targeted, effective, and safe therapeutic approaches for NF1. For this exploration-hypothesis development award, we hypothesize that expression of the RasL11A protein will block proliferation and induce death of human MPNST cells. Successful completion of this project will include animal work to test whether RASL11A is sufficient to induce MPNST regression. Positive results from this projec
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310958
Entities
People
- Raymond Mattingly
Organizations
- East Carolina University
- United States Army