Targeting the Mevalonate Pathway Suppresses VHL-Deficient CC-RCC through an HIF-Dependent Mechanism.

Clear cell renal cell carcinoma (CC-RCC) is a devastating disease with limited therapeutic options available for advanced stages. The objective of this study was to investigate HMG-CoA reductase inhibitors, also known as statins, as potential therapeutics for CC-RCC. Importantly, treatment with statins was found to be synthetically lethal with the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in 90% of CC-RCC driving the disease. This effect has been confirmed in three different CC-RCC cell lines with three different lipophilic statins. Inhibition of mevalonate synthesis by statins causes a profound cytostatic effect at nanomolar concentrations and becomes cytotoxic at low micromolar concentrations in VHL-deficient CC-RCC. The synthetic lethal effect can be fully rescued by both mevalonate and geranylgeranylpyrophosphate, but not by squalene, indicating that the effect is due to disruption of small GTPase isoprenylation and not the inhibition of cholesterol synthesis. Inhibition of Rho and Rho kinase (ROCK) signaling contributes to the synthetic lethality effect, and overactivation of hypoxia-inducible factor signaling resulting from VHL loss is required. Finally, statin treatment is able to inhibit both tumor initiation and progression of subcutaneous 786-OT1-based CC-RCC tumors in mice. Thus, statins represent potential therapeutics for the treatment of VHL-deficient CC-RCC. Mol Cancer Ther; 17(8); 1781-92. ©2018 AACR

Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271.

The question of whether tumorigenic cancer stem cells exist in human melanomas has arisen in the last few years. Here we show that in melanomas, tumour stem cells (MTSCs, for melanoma tumour stem cells) can be isolated prospectively as a highly enriched CD271(+) MTSC population using a process that maximizes viable cell transplantation. The tumours sampled in this study were taken from a broad spectrum of sites and stages. High-viability cells isolated by fluorescence-activated cell sorting and re-suspended in a matrigel vehicle were implanted into T-, B- and natural-killer-deficient Rag2(-/-)gammac(-/-) mice. The CD271(+) subset of cells was the tumour-initiating population in 90% (nine out of ten) of melanomas tested. Transplantation of isolated CD271(+) melanoma cells into engrafted human skin or bone in Rag2(-/-)gammac(-/-) mice resulted in melanoma; however, melanoma did not develop after transplantation of isolated CD271(-) cells. We also show that in mice, tumours derived from transplanted human CD271(+) melanoma cells were capable of metastatsis in vivo. CD271(+) melanoma cells lacked expression of TYR, MART1 and MAGE in 86%, 69% and 68% of melanoma patients, respectively, which helps to explain why T-cell therapies directed at these antigens usually result in only temporary tumour shrinkage

Targeting the RhoGTPase/ROCK pathway for the treatment of VHL/HIF pathway-driven cancers.

The loss of the von Hippel-Lindau (VHL) tumor-suppressor is a major driver of Clear Cell Renal Cell Carcinoma (CC-RCC) resulting in the stabilization and overactivation of hypoxia inducible factors (HIFs). ROCK1 is a well-known protein serine/threonine kinase which is recognized as having a role in cancer including alterations in cell motility, metastasis and angiogenesis. We recently investigated and identified a synthetic lethal interaction between VHL loss and ROCK1 inhibition in CC-RCC that is dependent on HIF overactivation. Increased expression and activity of both HIFs and ROCK1 occurs in many types of cancer supporting the potential therapeutic role of ROCK inhibitors beyond CC-RCC. We also discuss future research required to establish prognostic markers to predict tumor response to ROCK inhibitors

Writing Communities to (Re-)engage Faculty: The U See I Write Initiative

The COVID-19 pandemic has taken a toll on university faculty, unduly those from underrepresented groups, causing many faculty to disengage. Writing communities represent a promising tool to (re-)engage faculty and build an inclusive climate. As part of U See I Write, a faculty development initiative at the University of California, Irvine, we convened a series of monthly writing retreats between March and June of 2021, with between-retreat weekly writing sessions in smaller groups and an expectation to write daily for at least 30 minutes. In a diverse cohort of 34 faculty writers, program participation resulted in a significant increase in writing and work engagement. Similar initiatives at other institutions of higher education may prove successful in faculty (re-)engagement while also advancing faculty diversity

Writing communities to (re-) engage faculty: The U See I Write Initiative

The COVID-19 pandemic has taken a toll on university faculty, unduly those from underrepresented groups, causing many faculty to disengage. Writing communities represent a promising tool to (re-)engage faculty and build an inclusive climate. As part of U See I Write, a faculty development initiative at the University of California, Irvine, we convened a series of monthly writing retreats between March and June of 2021, with between-retreat weekly writing sessions in smaller groups and an expectation to write daily for at least 30 minutes. In a diverse cohort of 34 faculty writers, program participation resulted in a significant increase in writing and work engagement. Similar initiatives at other institutions of higher education may prove successful in faculty (re-)engagement while also advancing faculty diversity

Approaches to identifying synthetic lethal interactions in cancer.

Targeting synthetic lethal interactions is a promising new therapeutic approach to exploit specific changes that occur within cancer cells. Multiple approaches to investigate these interactions have been developed and successfully implemented, including chemical, siRNA, shRNA, and CRISPR library screens. Genome-wide computational approaches, such as DAISY, also have been successful in predicting synthetic lethal interactions from both cancer cell lines and patient samples. Each approach has its advantages and disadvantages that need to be considered depending on the cancer type and its molecular alterations. This review discusses these approaches and examines case studies that highlight their use

Approaches to identifying synthetic lethal interactions in cancer.

Targeting synthetic lethal interactions is a promising new therapeutic approach to exploit specific changes that occur within cancer cells. Multiple approaches to investigate these interactions have been developed and successfully implemented, including chemical, siRNA, shRNA, and CRISPR library screens. Genome-wide computational approaches, such as DAISY, also have been successful in predicting synthetic lethal interactions from both cancer cell lines and patient samples. Each approach has its advantages and disadvantages that need to be considered depending on the cancer type and its molecular alterations. This review discusses these approaches and examines case studies that highlight their use