DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Targeting P53-Associated Therapy Resistance in NF1-Related MPNSTs

Principal Investigator: STEENSMA, MATTHEW
Institution Receiving Award: VAN ANDEL RESEARCH INSTITUTE
Program: NFRP
Proposal Number: NF180089
Award Number: W81XWH-19-1-0483
Funding Mechanism: New Investigator Award - Early-Stage Investigator
Partnering Awards:
Award Amount: $855,000.00


PUBLIC ABSTRACT

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive cancers that are difficult to cure. If an individual with NF1 is diagnosed with an MPNST, clinicians have a difficult time deciding whether to use chemotherapy because few drugs actually help, and the side effects can be severe. The way MPNSTs develop chemotherapy resistance is not clear. We recently discovered a molecular signaling pathway that drives resistance to a drug called a MEK inhibitor. MEK is a key protein that regulates the RAS signaling pathway in cells. Because of the NF1 mutations that occur in neurofibromatosis, MEK is often hyperactivated and must be inhibited to kill a peripheral nerve tumor. MEK inhibitors are incredibly promising agents, but are equally prone to resistance as other chemotherapies. Thus, we are looking for optimal combination therapy partners. What is interesting is that a broad range of MPNST tumors all become resistant in a similar way when exposed to MEK inhibitors. Many appear to exhibit AKT activation within hours after MEK inhibitor treatment. This finding suggests that, if we effectively target the AKT compensation pathway before it is activated, we can sensitize a broad range of tumors to MEK inhibitors.

One of the critical pieces of information that is required to choose an effective therapy combination is to understand how tumor genetics influences the behavior of the therapy target. For instance, if an excessive amount of the MEK gene is present in a tumor cell, or if a mutation activates the MEK protein above its normal functional state, then it is likely that MEK will dominate the cellular signaling. If it becomes dominant, then it is also likely that we can kill the tumor by inhibiting the target. MPNSTs are genetically complex, which is to say that not one, but dozens of targetable genes are overabundant. This allows the tumor to quickly shift its signaling in response to our drugs and avoid death. We aim to better characterize MPNST genetic alterations and to study how the gene abnormalities affect signaling compensation within the tumor cells. In order to accomplish this goal, we developed a new way of studying MPNST genes of interest. Standard methods currently lack sensitivity to study the NF1 gene because it is incredibly large and structurally complex. To achieve an adequate level of sensitivity, each tumor must undergo a redundant form of sequencing analysis that costs thousands of dollars per sample. We developed a new technique in our laboratory that is more cost-effective and precise in determining the DNA sequence of MPNST genes. By utilizing this new technology, we will determine how genetic alterations influence the tumor’s response to MEK inhibitors and characterize human MPNST cell lines and tumor models so that other investigators can use this critical information for their own studies. Taken together, our research should have a profound impact on our understanding of MPNST genetics and therapy resistance. These studies are consistent with our research goal of increasing the survival of patients affected by NF1-related MPNSTs.