SUMMARY:
UCLA researchers in the Department of Molecular and Medical Pharmacology have discovered a class of small molecule that can be given to kidney cancer patients after surgical removal of their kidney tumor(s) to prevent metastasis and increase their survival rate.
BACKGROUND:
Kidney cancer is the 10th most common cancer worldwide, accounting for 2.4% of all cancers. The American Cancer Society estimates that, in the U.S. alone, there will be at least 79,000 new kidney cancer cases diagnosed and nearly 14,000 deaths attributed to kidney cancer in 2022. The 5-year survival rate for people with kidney cancer is 76%. However, survival rates depend on several factors, including the cell type and stage of cancer when it is first diagnosed. For the main type of kidney cancer, renal cell carcinoma (RCC), which accounts for 90% of cases, 80% are of the clear cell histological subtype (ccRCC), of which one-third are metastatic at the time of diagnosis. The 5-year survival rate for these patients with metastatic ccRCC is poor, around 10%, due to the lack of an effective treatment. While clinical trials of new treatments with tyrosine kinase inhibitors or immune checkpoint inhibitors have been promising, they have not yet led to a durable response. Therefore, new treatments to suppress metastasis could tremendously enhance care and survival rates for kidney cancer and other solid tumor types.
INNOVATION:
Researchers at UCLA led by Dr. Lily Wu have discovered a new class of drugs that can suppress metastasis in ccRCC. To do this, the UCLA researchers first discovered that metastasis in ccRCC involves cross communication between different populations of tumor cells within a tumor. They then used a high-throughput drug screen to identify several inhibitors that suppressed the growth and metastatic promoting activities of the metastasis-driving population of ccRCC tumor cells. For validation, the researchers developed novel metastatic ccRCC animal models, including new patient-derived metastatic ccRCC xenografts, and demonstrated the efficacy of the identified hit compounds in inhibiting metastasis in animal models. These drugs have the potential to prevent metastasis and offer long-term survival for kidney cancer patients.
POTENTIAL APPLICATIONS:
• Prevent metastasis of kidney cancer for improved survival rate
• Novel treatment method for solid tumors
ADVANTAGES:
• The small molecule selectively inhibits a signaling pathway that plays a large part in the mechanism of metastasis
• The lead hit compounds are already FDA approved
• The hit compounds are inexpensive
• Several of the identified hit compounds belong to the same class of small molecule drug, which has a long safety track record
DEVELOPMENT-TO-DATE:
The UCLA researchers have identified several small-molecule hit compounds in their high-throughput screen capable of inhibiting metastatic activity in cell culture and spontaneous lung metastasis in animal models of ccRCC. They have created reporter systems and tumor model systems for the validation of the efficacy of lead compounds.
Related Papers (from the inventors only):
Hu J, Schokrpur S, Archang M, Hermann K, Sharrow AC, Khanna P, Novak J, Signoretti S, Bhatt RS, Knudsen BS, Xu H, Wu L. A Non-integrating Lentiviral Approach Overcomes Cas9-Induced Immune Rejection to Establish an Immunocompetent Metastatic Renal Cancer Model. Mol Ther Methods Clin Dev. 2018 9:203-210. doi: 10.1016/j.omtm.2018.02.009. PMCID: PMC5948229
Schokrpur S, Hu J, Moughon DL, Liu P, Lin LC, Hermann K, Mangul S, Guan W, Pellegrini M, Xu H, Wu L. CRISPR-Mediated VHL Knockout Generates an Improved Model for Metastatic Renal Cell Carcinoma. Sci Rep. 2016 6:29032. doi: 10.1038/srep29032. PMCID: PMC4928183