Hem Onc Research Cancer Cell Biology

The laboratory of Clark W. Distelhorst, MD focuses on the role of the anti-apoptotic protein Bcl-2 in regulating the viability of cancer cells and the role of the tumor-associated extracellular microenvironment stimulating Bcl-2 elevation. The lab discovered that Bcl-2 interacts with the inositol 1,4,5-trisphosphate receptor (IP3R) calcium channel and developed a peptide inhibitor of this interaction. Through high throughput screening, they recently identified several drug-like compounds that in preliminary studies function like their peptide to induce calcium-mediated apoptosis in primary human CLL cells. Also, they are developing nanoparticles to deliver their Bcl-2-inhibitory peptide into cancer cells. In related studies, they discovered that a G protein-coupled receptor, GPR65, is activated by reduced extracellular pH and signals Bcl-2 upregulation, thereby promoting survival of cancer cells in the acidic extracellular tumor microenvironment. Finally, work in the Distelhorst lab will lead to novel therapeutic approaches by defining novel therapeutic targets.

The laboratory of Shigemi Matsuyama, PhD, also focuses on cell death regulation and in so doing discovered that the DNA damage repair protein Ku70 regulates cell death by binding to and thereby inhibiting the proapoptotic protein Bax. They have developed a novel peptide that inhibts Ku70-Bax interaction. This Bax Inhibiting Peptide, or BIP, protects normal cells from cytotoxic stresses and rescues neurons from beta-amyloid accumulation, a contributor to Alzheimer disease. Also, BIP protects megakaryocytes from the chemotherapy-induced cell death, suggesting that BIP may be able to reduce chemotherapy-induced thrombocytopenia. Furthermore, Dr. Matsuyama’s group discovered that knocking out Ku70 causes premature aging in mice and that this is partially prevented by also knocking out Bax, suggesting that Bax-mediated apoptosis plays a role aging. In addition to this groundbreaking work, the lab also discovered that IFNgR2 (interferon gamma receptor 2) also interacts with Bax and regulates its proapoptotic function. They find abnormally high levels of IFNgR2 in prostate cancer and melanoma and have evidence that it plays a role in the resistance of these tumors to apoptosis. In summary, Dr. Matsuyama’s identification of new Bax suppressors provides a unique opportunity to develop novel cancer therapeutics.

Research in the laboratory of C.K. Qu, PhD, is devoted to understanding the molecular mechanisms by which gain of function (GOF) mutations of protein tyrosine phosphatase Ptpn11 (Shp2) cause malignancies. These mutations, implicated in multiple cell signaling pathways, have been identified in childhood leukemias and solid tumors. Dr. Qu’s work demonstrated that Ptpn11 mutations play initiating roles in leukemogenesis. His group has recently found that these mutations cause chromosomal instability and aneuploidy by disturbing mitosis and cytokinesis, and increase susceptibility to DNA damage-induced malignancies. Specific mutations, they find, compromise the mitotic checkpoint function. Aberrant mitosis with chromosomal missegregation and centrosome amplification is increased in Ptpn11 mutant cells. These phenotypes are exacerbated by gamma-irradiation. Time-lapse microscopic analyses show that the duration of mitosis is prolonged and that abnormal cytokinesis is markedly increased in Ptpn11 mutant cells. Furthermore, they have discovered that Shp2 is distributed to the kinetochore, centrosome, spindle midzone, and midbody that play critical roles in mitosis and cytokinesis. Mitotic kinases Plk1 and Aurora B are hyperactivated by Ptpn11 GOF mutations. These studies reveal a previously unrecognized role for Shp2 phosphatase in the maintenance of genomic stability and provide novel insights into the mechanism by which Ptpn11 GOF mutations induce malignancies. Their findings have important clinical implications. Since Ptpn11 GOF mutations enhance DNA damage-induced carcinogenesis, caution should be taken when using whole body irradiation and chemotherapy in Ptpn11-associated hematologic malignancies, especially for those patients with germline mutations in Ptpn11, since the risk of therapy-induced malignancies in these patients may be increased.

The lab of Afshin Dowlati, MD, has two main themes: PIAS3 as a tumor suppressor in non-small-cell lung cancer (NSCLC) and development of new therapeutic approaches to small-cell lung cancer (SCLC). PIAS3 is an endogenous inhibitor of STAT3 that shows decreased expression in NSCLC, particularly squamous cell (SCC). Their findings suggest that PIAS3 is regulated at the level of protein translation or stability and accordingly they are attempting to find drugs that increase endogenous PIAS3 expression in SCC cell lines. In SCLC, they have an established collaboration with Jill Barnholtz-Sloan to use bioinformatics to analyze publicly-available databases of comprehensive drug screens and thereby identify drugs effective agains SCLC and at the same time identify gene expression signatures or other genomic features that predict drug sensitivity, with current focus on PLK inhibitors. They have also started looking for genomic mutations in FFPE and frozen SCLC tumors by CNV, WES and RNAseq analyses. Current focus is on an activating mutation found in the RET tyrosine kinase receptor. They have established a collaboration with David MacPherson, a mouse geneticist at Fred Hutchinson and Peter Scacheri at Case for these studies.