Michael E. Hurwitz

C. elegans CARMIL negatively regulates UNC-73/Trio function during neuronal development

Whereas many molecules that promote cell and axonal growth cone migrations have been identified, few are known to inhibit these processes. In genetic screens designed to identify molecules that negatively regulate such migrations, we identified CRML-1, the C. elegans homolog of CARMIL. Although mammalian CARMIL acts to promote the migration of glioblastoma cells, we found that CRML-1 acts as a negative regulator of neuronal cell and axon growth cone migrations. Genetic evidence indicates that CRML-1 regulates these migrations by inhibiting the Rac GEF activity of UNC-73, a homolog of the Rac and Rho GEF Trio. The antagonistic effects of CRML-1 and UNC-73 can control the direction of growth cone migration by regulating the levels of the SAX-3 (a Robo homolog) guidance receptor. Consistent with the hypothesis that CRML-1 negatively regulates UNC-73 activity, these two proteins form a complex in vivo. Based on these observations, we propose a role for CRML-1 as a novel regulator of cell and axon migrations that acts through inhibition of Rac signaling.

SLI-1 Cbl Inhibits the Engulfment of Apoptotic Cells in C. elegans through a Ligase-Independent Function

The engulfment of apoptotic cells is required for normal metazoan development and tissue remodeling. In Caenorhabditis elegans, two parallel and partially redundant conserved pathways act in cell-corpse engulfment. One pathway, which includes the small GTPase CED-10 Rac and the cytoskeletal regulator ABI-1, acts to rearrange the cytoskeleton of the engulfing cell. The CED-10 Rac pathway is also required for proper migration of the distal tip cells (DTCs) during the development of the C. elegans gonad. The second pathway includes the receptor tyrosine kinase CED-1 and might recruit membranes to extend the surface of the engulfing cell. Cbl, the mammalian homolog of the C. elegans E3 ubiquitin ligase and adaptor protein SLI-1, interacts with Rac and Abi2 and modulates the actin cytoskeleton, suggesting it might act in engulfment. Our genetic studies indicate that SLI-1 inhibits apoptotic cell engulfment and DTC migration independently of the CED-10 Rac and CED-1 pathways. We found that the RING finger domain of SLI-1 is not essential to rescue the effects of SLI-1 deletion on cell migration, suggesting that its role in this process is ubiquitin ligase-independent. We propose that SLI-1 opposes the engulfment of apoptotic cells via a previously unidentified pathway.

Chemotherapy in Prostate Cancer

For approximately a decade, chemotherapy has been shown to prolong life in patients with metastatic castration-resistant prostate cancer (mCRPC). Since that time, however, only two agents have proven to prolong life (docetaxel and cabazitaxel). However, in the last year, the addition of chemotherapy to primary hormonal therapy became a standard of care for high-volume castration-sensitive metastatic disease. Here I will review current prostate cancer chemotherapies, mechanisms of resistance to those therapies, and ongoing clinical studies of chemotherapy combinations and novel chemotherapeutics.

Cancer immunotherapy: new applications in urologic oncology.

Purpose of review Over the last 10 years, harnessing of the immune system to attack tumors has been one of the major breakthroughs in cancer, primarily through the use of immune checkpoint inhibitors (ICIs). This review will summarize current immune treatments in urologic malignancies and ongoing trials with novel combinations and in different disease settings. Recent findings Patients with urologic malignancies such as kidney and bladder cancer have benefited significantly from these advances with the approval of ICIs in both of these diseases. In addition, older immune therapies have also been used in these malignancies. For example, kidney cancers, which are traditionally unresponsive to chemotherapy, can respond to immune activation by cytokines. Prostate cancers, too, have immune therapies, such as sipuleucel-T, a dendritic cell vaccine. Combining ICIs with these older treatments as well as with molecularly targeted therapies and chemotherapies are currently underway. Summary The ICIs have changed the way urologic malignancies are treated and newer combinations are likely to alter the therapeutic landscape in these diseases dramatically in the coming years.

Multicenter Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib in Patients With Metastatic or Unresectable Transitional-Cell Carcinoma

Background: Sorafenib, an oral tyrosine kinase inhibitor, may enhance the antitumor activity of platinum‐based chemotherapy in transitional‐cell carcinoma. This study investigated the safety and clinical outcome of adding sorafenib to gemcitabine and carboplatin for patients with advanced transitional‐cell carcinoma. Patients and Methods: Subjects with metastatic or unresectable chemotherapy‐naive TCC with Eastern Cooperative Oncology Group performance status 0 or 1 received gemcitabine (1000 mg/m2 on days 1 and 8) and carboplatin (area under the curve of 5 on day 1) with sorafenib (400 mg 2 times a day on days 2‐19 every 21 days) for 6 cycles. Subjects with stable disease or partial or complete response continued to receive sorafenib until disease progression. The primary end point was progression‐free survival (PFS) at 5 months with a secondary end point of response (partial or complete). Results: Seventeen subjects were enrolled. The median number of cycles of gemcitabine and carboplatin with sorafenib provided was 4.4. A total of 15, 5, and 8 subjects required reductions of gemcitabine, carboplatin, and sorafenib, respectively. Thirteen subjects (76%) required multiple dose reductions. Eleven subjects (65%) were free of progression at 5 months. The overall response rate was 54% (95% confidence interval [CI], 0.28‐077), with 4 patients experiencing complete response (24%; 95% CI, 0.07‐0.50) and 5 partial response (29%; 95% CI, 0.10‐0.56); 7 subjects (41%) had stable disease. Median PFS was 9.5 months (95% CI, 0.43‐1.26), and median overall survival was 25.2 months (95% CI, 0.96‐5.65). One‐year PFS was 31%, and 1‐year overall survival was 72%. Eleven subjects (65%) discontinued treatment because of toxicity. There were no toxic deaths. Conclusion: Gemcitabine and carboplatin with sorafenib showed clinical activity in advanced TCC, with some prolonged progression‐free intervals. However, gemcitabine and carboplatin with sorafenib was associated with significant toxicity, causing discontinuation of therapy in most patients.

Clonal screens to find modifiers of partially penetrant phenotypes in C. elegans.

Unbiased genetic screens are an excellent way to discover novel genes involved in specific biological processes in vivo. Modifier screens, whether to suppress or enhance a phenotype, are a powerful way to find proteins that modulate biological processes responsible for specific phenotypes. However, modification of phenotypes that are only partially penetrant, which is often the case, are often extremely difficult to screen this way in a traditional F2 or non-clonal genetic screen. Here we describe an F3 or clonal screen in the nematode Caenorhabditis elegans to search for genes that modify partially penetrant phenotypes. Specifically we describe a screen to search for modifiers of genes that cause defects in migration of a specific developmentally regulated cell, the distal tip cell.