Combination of Erlotinib and Naproxen Employing Pulsatile or Intermittent Dosing Profoundly Inhibits Urinary Bladder Cancers

Abstract

Daily dosing of either NSAIDs or EGFR inhibitors has been shown to prevent bladder cancer development in a N-butyl-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced rat model. However, these inhibitors cause gastrointestinal ulceration and acneiform rash, respectively, limiting their continuous use in a clinical prevention setting. We studied chemopreventive efficacy of pulsatile dosing of EGFR inhibitor erlotinib (42 mg/kg BW, once/week) combined with intermittent or continuous low doses of the NSAID naproxen (30 mg/kg BW/day, 3 weeks on/off or 128 ppm daily in diet) in the OH-BBN induced rat bladder cancer model. The interventions were started either at 1 or 4 weeks (early intervention) or 3 months (delayed intervention) after the last OH-BBN treatment, by which time the rats had developed microscopic bladder lesions. All combination regimens tested as early versus late intervention led to the reduction of the average bladder tumor weights (54%–82%; P < 0.01 to P < 0.0001), a decrease in tumor multiplicity (65%–85%; P < 0.01 to P < 0.0001), and a decrease in the number of rats with large palpable tumors (>200 mg; 83%–90%; P < 0.01 to P < 0.0001). Levels of signal transduction markers, Ki-67, cyclin D1, IL1β, pSTAT3, and pERK, were significantly (P < 0.05 to P < 0.001) reduced in the treated tumors, demonstrating their potential utility as predictive markers for efficacy. These findings demonstrate that significant chemopreventive efficacy could be achieved with alternative intervention regimens designed to reduce the toxicity of agents, and that starting erlotinib and/or naproxen treatments at the time microscopic tumors were present still conferred the efficacy.

Efficacy of EGFR Inhibitors and NSAIDs Against Basal Bladder Cancers in a Rat Model: Daily vs. Weekly Dosing, Combining EGFR Inhibitors with Naproxen, and Effects on RNA Expression

“…In summary, the combination of an EGFR inhibitor and an NSAID is an excellent candidate for treatment of basal bladder cancer. We have confirmed these results in the OHBBN-induced bladder cancer model employing the combination of erlotinib and naproxen [21]. Furthermore, the combination erlotinib plus sulindac has proven highly effective clinically in an FAP trial [23] which should offer clear ideas regarding likely toxicities of such a combination.…”

Chemoprevention of Urothelial Cell Carcinoma Tumorigenesis by Dietary Flavokawain A in UPII-Mutant Ha-ras Transgenic Mice

“…We have shown that FKA preferentially inhibited the growth of HER2-overexpressing breast cancer cell lines (i.e., SKBR3 and MCF7/HER2) versus those with less HER2 expression (i.e., MCF7 and MDA-MB-468) through inhibition of Cdc2 and Cdc25C phosphorylation and downregulation of expression of Myt1 and Wee1 [ 22 ]. To more efficiently inhibit tumor growth in NMIBC, combination approaches of FKA with RAS-targeting drugs (e.g., sotorasib and salirasib) [ 23 , 24 ], FGFR-3 inhibitor (e.g., erdafitinib) [ 25 ], and EGFR inhibitors (e.g., erlotinib and gefitinib) [ 26 , 27 ] should be further explored.…”

Metformin Can Enhance the Inhibitory Effect of Olaparib in Bladder Cancer Cells

“…At present, the treatment of bladder cancer is mostly a combination of surgery and chemotherapy. The most effective way to prevent postoperative recurrence of bladder cancer patients is to supplement the intravesical infusion of immunosuppressants or chemotherapy drugs after surgery, but the recurrence rate of the tumor after surgery is as high as 60-70% [22,23]. The severe side effects limit its clinical application.…”