Current projects
The goal of our research is to discover new therapies that will eliminate, rather than slow down, the tumor cells in TSC and LAM patients. To do that we follow two approaches: a targeted approach in which we evaluate specific candidates we believe are involved in TSC and LAM tumor cell pathogenesis, and a screen approach in which we evaluate hundreds of known drugs for their ability to kill TSC and LAM tumor cells.
Targeting Polo-like kinase 1 (PLK1) for TSC and LAM
Polo-like kinase 1 (PLK1) is a protein that is essential for cell division. It is known that various cancer types, including breast, colorectal, pancreatic and prostate. Currently several drugs targeting PLK1 in cancer patients are in clinical trials.
Previously we found a connection between PLK1 and the TSC1 and TSC2 proteins, that are mutated in TSC and LAM, and very recently we found that PLK1 inhibitors selectively inhibit cells without TSC1 or TSC2, compared to control cells (Valianou et al. 2015 Cell Cycle).
Pharmacological inhibition of PLK1 decreases the viability of hamartin and tuberin deficient cells. (A) Tsc1+/− andTsc1−/− MEF and (B) Tsc2+/+/Tp53−/− and Tsc2−/−/Tp53−/− MEF, were treated with BI-2536 for 4 days, viability was measured by MTT conversion, and normalized to vehicle-treated controls (n = 8; ** indicates P < 0.01; *** indicates P < 0.001). (from Valianou et al. 2015 Cell Cycle)
We now evaluate Volasertib, a PLK1 inhibitor from Boehringer Ingelheim in phase II/III clinical trials for advanced solid tumors and leukemias, in animal models relevant to LAM and TSC. Specifically, we will test if Volasertib stops tumor growth and lung metastasis, if it causes cell death in tumor cells in animals, and if tumors regrow after we stop treatment. This study is partially funded through a pilot project grant from the University of Pennsylvania Orphan Disease Center (see Funding).
Targeting Polo-like kinase 1 (PLK1) for TSC and LAM
Polo-like kinase 1 (PLK1) is a protein that is essential for cell division. It is known that various cancer types, including breast, colorectal, pancreatic and prostate. Currently several drugs targeting PLK1 in cancer patients are in clinical trials.
Previously we found a connection between PLK1 and the TSC1 and TSC2 proteins, that are mutated in TSC and LAM, and very recently we found that PLK1 inhibitors selectively inhibit cells without TSC1 or TSC2, compared to control cells (Valianou et al. 2015 Cell Cycle).
Pharmacological inhibition of PLK1 decreases the viability of hamartin and tuberin deficient cells. (A) Tsc1+/− andTsc1−/− MEF and (B) Tsc2+/+/Tp53−/− and Tsc2−/−/Tp53−/− MEF, were treated with BI-2536 for 4 days, viability was measured by MTT conversion, and normalized to vehicle-treated controls (n = 8; ** indicates P < 0.01; *** indicates P < 0.001). (from Valianou et al. 2015 Cell Cycle)
We now evaluate Volasertib, a PLK1 inhibitor from Boehringer Ingelheim in phase II/III clinical trials for advanced solid tumors and leukemias, in animal models relevant to LAM and TSC. Specifically, we will test if Volasertib stops tumor growth and lung metastasis, if it causes cell death in tumor cells in animals, and if tumors regrow after we stop treatment. This study is partially funded through a pilot project grant from the University of Pennsylvania Orphan Disease Center (see Funding).
Role of PLK1 in regulation of cancer cell survival
PLK1 is implicated in various aspects of cell physiology. New insights suggest that it plays an important role in cell survival, and the cell survival/cell death decision We are exploring the mechanisms by which PLK1 may affect autophaty, a critical cell survival mechanism for cancer cells.
PLK1 is implicated in various aspects of cell physiology. New insights suggest that it plays an important role in cell survival, and the cell survival/cell death decision We are exploring the mechanisms by which PLK1 may affect autophaty, a critical cell survival mechanism for cancer cells.
Screening of FDA-approved drugs for TSC and LAM
Through a Drug Screening Program grant from the Tuberous Sclerosis Alliance, we screened 88 FDA-approved drugs for oncology for their ability to differentially decrease the viability of TSC1 and TSC2 cells, compared to controls. We identified 8 drugs with at least two-fold inhibition of TSC1 and TSC2 null cells, and validated these results in secondary analyses. We now perform additional screens to identify drug combinations for pre-clinical evaluation in animal models.
Through a Drug Screening Program grant from the Tuberous Sclerosis Alliance, we screened 88 FDA-approved drugs for oncology for their ability to differentially decrease the viability of TSC1 and TSC2 cells, compared to controls. We identified 8 drugs with at least two-fold inhibition of TSC1 and TSC2 null cells, and validated these results in secondary analyses. We now perform additional screens to identify drug combinations for pre-clinical evaluation in animal models.