Posted September 14, 2016

Through an FY07 Concept Award from the Ovarian Cancer Research Program (OCRP), Dr. Laurie Hudson and Dr. Angela Wandinger-Ness, from the University of New Mexico, and their collaborators identified dysregulated small Rho-family GTPases Rac1 and Cdc42 as key players in upregulating cell adhesion, migration, and invasion in ovarian cancer.  They hypothesized that inhibiting the activity of Rac1 and Cdc42 could potentially halt tumorigenesis and metastasis.  The team, including bioinformatics and high content screening experts Drs. Tudor Oprea and Larry Sklar, found that ketorolac (R-ketorolac) and naproxen (R-naproxen), FDA-approved NSAIDS, were capable of inhibiting Rac1 and Cdc42 and thereby impeding ovarian cancer cell metastasis. 

With the FY11 Teal Expansion Award, Dr. Hudson and Dr. Wandinger-Ness expanded their understanding of naproxen and ketorolac as potential ovarian cancer drug treatments by elucidating the inhibition mechanism, evaluating the drugs’ efficacy, and initiating pilot clinical trials led by OB/Gyn oncologist Dr. Carolyn Muller.  They demonstrated in animal and human cell culture assays that naproxen and ketorolac inhibited activated Rac1 and Cdc42 GTPase when cells were stimulated with epidermal growth factors.  Additional binding assays and flow cytometry revealed that ketorolac blocks the GTPase signaling cascade in ovarian cancer cells by inhibiting phosphorylation and thereby reducing effector activations downstream of Rac1 and Cdc42.  Further studies in human cells showed that ketorolac prevented the formation of invadopodia structures which are used to invade neighboring tissues and metastasis.  Efficacy studies in ovarian cancer cells showed that ketorolac and naproxen decreased cancer cell adhesion, invadopodia length and number, migration, and invasion without inducing detectable cytotoxicity.  In vivo studies in xenograft models confirmed reduction of tumor burden after ketorolac treatment.  A pilot clinical trial also demonstrated that postoperative administration of ketorolac (Toradol®), a racemic mixture of R,S ketorolac, in debulked advanced stage ovarian cancer patients decreased Rac1 and Cdc42 activity found in ascites and patient-derived ovarian tumor cells.  The pilot clinical trial also showed that administration of ketorolac reduced cell adhesion to fibronectin or collagen, a sign suggesting tumor implantation reduction and metastasis inhibition.

Altogether, the results from these two OCRP-funded projects forged the rationale for a randomized, placebo-controlled study: Effects of Ketorolac after Surgery in Patients with Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (Trial IDs: INST 1420, NCI-2015-01081, 15-049, NCT02470299).  Because this study focuses on repurposing an already FDA-approved drug, promising data from the clinical trial may be rapidly translated, giving ovarian cancer patients access to a targeted treatment not currently available.  Through their research, Drs. Hudson and Wandinger-Ness bring to light the promise of a valuable treatment option that could prove beneficial to many ovarian cancer patients battling further tumorigenesis and metastasis.

Publications:

Guo Y, Kenney SR, Cook L, Adams SF, Rutledge T, Romero E, Oprea TI, Sklar LA, Bedrick E, Wiggins CL, Kang H, Lomo L, Muller CY, Wandinger-Ness A, and Hudson LG.  2015.  A novel pharmacologic activity of ketorolac for therapeutic benefit in ovarian cancer patients.  Clin Cancer Res 21(22):5064-5072.  

Guo Y, Kenney SR, Muller CY, Adams S, Rutledge T, Romero E, Murray-Krezan C, Prekeris R, Sklar LA, Hudson LG, and Wandinger-Ness A.  2015.  R-ketorolac targets Cdc42 and Rac1 and alters ovarian cancer cell behaviors critical for invasion and metastasis.  Mol Cancer Ther 14(10):2215-2227.  

Oprea TI, Sklar LA, Agola JO, Guo Y, Silberberg M, Roxby J, Vestling A, Romero E, Surviladze Z, Murray- Krezan C, Waller A, Ursu O, Hudson LG, and Wandinger-Ness A.  2015.  Novel activities of select NSAID R-Enantiomers against Rac1 and Cdc42 GTPases.  PLoS One 10(11):e0142182.  

Links:

Public and Technical Abstracts: Inhibition of Small GTPases as a Novel Therapeutic Approach in Ovarian Cancer

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