Page 39 - Annual Report 2020

Melanoma: Melanoma is the most dangerous form of skin cancer. According to the CDC, Minnesota has the highest incidence of melanoma in midwest states. Despite advances in melanoma research, the five-year survival
rate for patients with advanced melanoma remains around 16%. Two therapeutic agents, vemurafenib, and dabrafenib, are FDA-approved for the treatment of advanced melanomas that carry BRAFV600E mutations. Although the initial response to these inhibitors can be dramatic, the melanomas nearly always become resistant. Using a novel in vivo model of melanoma
we have developed provides an exceptional experimental system to study this issue. We are determining and validating the mechanisms of melanoma’s resistance to these inhibitors. This year we discovered and published that BRAF inhibition in melanoma is associated with the dysregulation of histone methylation and histone methyltransferases in the journal Neoplasia. This work is generously funded through an American Cancer Society Research Scholar Grant worth nearly $800,000. The American Cancer Society is the largest nonprofit source of grant funding for cancer researchers in the United States, other than the government.
Glioma: Gliomas are the most common primary brain tumor. Glioblastoma (GBM), the highest grade of glioma (most lethal), is highly infiltrative, and is resistant to all conventional therapies. Patients with this cancer rarely survive longer than 12-14 months from the time the tumor is diagnosed. Pediatric GBM is clinically and biologically distinct from the adult disease. It typically develops in the midline or pons. While even the lowest grade of glioma in
children pilocytic astrocytoma is associated with significant morbidity diffuse intrinsic pontine glioma (DIPG), a GBM of the brain stem confers the worst prognosis of any pediatric cancer. It
has a 5-year survival rate of <1%, a 1-year survival of <30% and 2 -year survival of <10 %; median survival is < 9 months. Pediatric GBM is defined by mutations in the gene encoding Histone H3.3. We are developing an animal model to study this disease. In collaboration with the Hinchcliffe lab at the Hormel Institute, we seek to bring about a better understanding of the role of this mutation in these tumors in order to develop new therapies to improve survival for children with this devastating disease. This work is generously funded by
an award from the Minnesota Partnership for Biotechnology and Medical Genomics.
Colon Cancer: After lung and prostate cancer, colon cancer is the leading cause of cancer deaths in the United States with 132,770 new cases and 49,700 deaths anticipated in 2015. About 75% of cases are sporadic with no obvious evidence of an inherited disorder. The remaining 25% of patients have a family history of CRC
that suggests a hereditary contribution, common exposures among family members, or a combination of both. Familial adenomatous polyposis (FAP), is one of the most clearly defined and well understood of the inherited colon cancer syndromes. Our preliminary
data has demonstrated that loss of APC is insufficient for tumorigenesis and additional growth signals or mutations are also required for nuclear accumulation of β-catenin and intestinal polyposis. Since in vivo models of FAP develop a multitude of intestinal polyps without additional genetic alterations, these additional
signals are likely to arise from adjacent stromal cells. If we can show that stromal signaling plays a driving role in tumorigenesis, following or pre-empting epithelial LOH of APC, it should be possible to develop targeted therapeutics to block this signaling. A major preliminary finding is that heterozygous mutation of APC in adult in vivo is not sufficient to cause tumor formation. Our sections work on colon cancer has been funded by the National Institutes of Health (NIH) and our ongoing studies will contribute to the development of novel therapies and improve
the outcome for patients with colon cancer.
THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 39