Chemoprevention and Breast Cancer

The Grubbs Lab’s research has traditionally focused on the development of chemically induced cancer models in rodents; and how they could be used to screen new chemopreventive agents, and to evaluate the effects of endocrine modification on mammary carcinogenesis.

In one such study, the efficacy of a new RXR specific retinoid (9cUAB30) when combined with tamoxifen in the prevention of mammary cancer was determined. When administered by gavage, 9cUAB30 was rapidly absorbed. A four-week dose selection study in which the rexinoid was given at various dose levels revealed fairly constant serum levels regardless of dose or length of treatment; probably accounting for the low toxicity of this compound. When suboptimal doses of 9cUAB30 and tamoxifen were given in the methylnitrosourea (MNU) mammary cancer model, both agents reduced cancer multiplicity by 30-35 percent, while the combination of the agents reduced cancer numbers by 57 percent. This suggested that different pathways were altered by the agents. Recently, additional studies have shown greater detail of the mechanism of action for 9cUAB30 and that the agent can possibly be used in the clinic for breast cancer prevention.

Publications

  1. Grubbs, C.J., Hill, D.L., Bland, K.I., Beenken, S.W., Lin, T-H., Eto, I., Atigadda, V.R., Vines, K.K., Brouillette, W.J., & Muccio, D.D. (2003). 9-cUAB30, an RXR specific retinoid, and/or tamoxifen in the prevention of methylnitrosourea-induced mammary cancers. Cancer Letters, 201: 17-24.
  2. Grubbs, C.J., Lubet, R.A., Atigadda, V.R., Christov, K., Deshpande, A.M., Tirmal, V., Xia, G., Bland, K.I., Eto, I., Brouillette, W.J., & Muccio, D.D. (2006). Efficacy of new retinoids in the prevention of mammary cancers and correlations with short-term biomarkers. Carcinogenesis, 27: 1232-39.
  3. Lubet, R.A. (2013). Effects of gene expression in rat livers after administration of RXR Agonists: UAB30, 4-Methyl-UAB30, and Targretin (Bexarotene). Molecular Pharmacology, 83: 698-708. Kolesar, J.M., Hoel, R., Pomplun, M., Havighurst, T., Stublaski, J., Wollmer, B., Krontiras, H., Brouillette, W., Muccio, D.D., Kim, K., Grubbs, C.J., & Bailey, H.E. (2010). A pilot, first-in-human, pharmacokinetic study of 9cUAB30 in healthy volunteers. Cancer Prevention Research, 3: 1565-70.

NSAIDs and Urinary Bladder Cancer

More recently, the Grubbs Lab has been involved in screening multiple classes of compounds for efficacy in prevention of urinary bladder cancer. Epidemiological studies have shown that non-steroid, anti-inflammatory drugs (NSAIDs) have a role in the prevention of human cancers. Specifically, the Grubbs Lab initially demonstrated that one NSAID, celecoxib, was highly effective in preventing carcinogen-induced urinary bladder cancers in both rats and mice. These cancers are highly invasive and are histologically similar to human transitional cell carcinoma. The cancers appear by array analysis to have strong overlap with human bladder cancer, both at the pathway level and at the specific gene level. One such study from the Grubbs Lab recently showed that continuous treatment with a chemopreventive agent may not be necessary, possibly eliminating the long-term toxicity of an agent. The lab showed that intermittent dosing (one week on/one week off or three weeks on/three weeks off) with naproxen was equally as effective in preventing urinary bladder cancers as continuous dosing, thereby potentially eliminating the gastric toxicity of this agent in humans.

Publications

  1. Grubbs, C.J., Lubet, R.A., Atigadda, V.R., Christov, K., Deshpande, A.M., Tirmal, V., Xia, G., Bland, K.I., Eto, I., Brouillette, W.J., Muccio, D.D. Efficacy of new retinoids in the prevention of mammary cancers and correlations with short-term biomarkers. Carcinogenesis, 27: 1232-39, 2006.
  2. Steele, V.E., Rao, C.V., Zhang, Y., Patiolla, J., Boring, D., Kopelovich, L., Juliana, M.M., Grubbs, C.J., and Lubet, R.A. Chemopreventive efficacy of naproxen and nitric oxide-naproxen in rodent models of colon, urinary bladder, and mammary cancers. Cancer Prev Res: 11: 951-56, 2009.
  3. Lubet, R.A., Steele, V.E., Juliana, M.M., and Grubbs, C.J. Screening agents for preventive efficacy in a bladder cancer model: study design, end points, and gefitinib and naproxen efficacy. J Urol: 183, 1598-1603, 2010.
  4. Lubet, R.A., Scheiman, J.M., Bode, A., White, J., Minasian, L., Juliana, M.M., Boring, D.l., Steele, V.E., and Grubbs, C.J. Prevention of Chemically-Induced Urinary Bladder Cancers by Naproxen: Protocols to Reduce Gastric Toxicity in Humans Do Not Alter Preventive Efficacy. Cancer Prev Res. 8:296-302, 2015.
  5. Waters, A.M., Stewart, J.E., Atigadda, V.R., Mroczek-Musulman, E., Grubbs, C.J.,and Beirerle, E.A. Preclinical Evaluation of UAB30 in Pediatric Renal and Hepatic Malignancies. Mol Cancer Ther. 15: 911, 2016.