Date of Degree

2-2019

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Maria Contel

Committee Members

Guillermo Gerona-Navarro

Karen Hubbard

Mara Schvarzstein

Joe Ramos

Subject Categories

Biology

Keywords

Renal cancer, metallodrugs, gold, ruthenium, heterobimetallic, kidney cancer

Abstract

Renal cell carcinomas (RCCs) remain a significant health concern in the United States because of a lack of effective treatment. To date, RCCs account for 2.4% of all cancer deaths in the United States, and about 14,970 people will die from the disease in 2018, mostly of advanced or metastasized RCCs1,2. Mutations in metabolic pathways are characteristics of RCCs, including changes in redox metabolism, deregulation of proteolytic factor expression, and inflammation. These molecular events promote tumor vascularization, growth, invasion, and metastasis, which often correlate with a poor prognosis. Many pharmaceutical avenues have been explored, including cytotoxic chemotherapeutics, biologics targeting cellular pathways, and immune therapies administered as mono- or combination therapies; all with very modest success in treatment of the advanced disease, and most are associated with significant adverse events3,4. The absence of viable treatment options has led to a resurgence of interest in unconventional metal-based drugs that have shown some potential in the treatment of RCCs5–8. The conception of molecules containing two different metals with known anticancer properties to potentiate their cytotoxic effect is recent, and studies suggest that this approach may be ii successful9,10. In our group, a series of heterobimetallic compounds containing gold-titanium or gold-ruthenium were synthesized and progressively modified to optimize their stability, bioavailability, and cytotoxicity 11–13. After screening a series of novel bimetallic complexes and their monometallic moieties against an array of cancerous cell lines, we were able to substantiate our assertion that gold drives the potent efficacy of the complexes. From these screens, three promising candidates emerged: (gold-titanium) Titanocref and Titanofin and (gold-ruthenium) RANCE-1. For those compounds, mechanistic and efficacy studies were carried out in vitro and in a mouse model of RCC. We found that our novel gold-titanium and gold-ruthenium compounds were highly cytotoxic to ccRCC cells, were selective for tumor cells, and inhibited molecular markers associated with advanced ccRCC malignancies such as invasion and angiogenesis at subtoxic concentrations. In vivo the complexes induced significant tumor shrinkage in the case of Titanocref and Titanofin or exhibited chemo-static effects in the case of RANCE-1. We also obtained pharmacokinetic and pathology reports indicating that the compounds were deposited in tumors and that they caused no chronic systemic toxicity. This body of work from my doctoral research, indicates that these three novel metallodrug complexes are viable candidates for further preclinical development.

Bibliography

1. The American Cancer Society. Cancer Facts and Figures 2018. American Cancer Society (2018). Available at: https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html. (Accessed: 25th July 2018)

2. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2017. CA. Cancer J. Clin. 67, 7–30 (2017).

3. Ciccarese, C. et al. Addressing the best treatment for non-clear cell renal cell carcinoma: A metaanalysis of randomised clinical trials comparing VEGFR-TKis versus mTORi-targeted therapies. Eur. J. Cancer 83, 237–246 (2017).

4. Motzer, R. J. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–456 (2008).

5. Diamond, E. et al. Cytotoxic chemotherapy in the treatment of advanced renal cell carcinoma in the era of targeted therapy. Critical Reviews in Oncology/Hematology 96, 518–526 (Elsevier, 2015).

6. Hsieh, J. J. et al. Renal cell carcinoma. Nat. Rev. Dis. Prim. 3, 17009 (2017).

7. Strohfeldt, K. & Tacke, M. Bioorganometallic fulvene-derived titanocene anti-cancer drugs. Chem. Soc. Rev. 37, 1174 (2008).

8. Serratrice, M. et al. Cytotoxic gold compounds: synthesis, biological characterization and investigation of their inhibition properties of the zinc finger protein PARP-1. Dalt. Trans. 41, 3287 (2012).

9. González-Pantoja, J. F. et al. Titanocene-phosphine derivatives as precursors to cytotoxic heterometallic TiAu 2 and TiM (M = Pd, Pt) compounds. Studies of their interactions with DNA. Inorg. Chem. 50, 11099–11110 (2011).

10. Lease, N. et al. Potential Anticancer Heterometallic Fe–Au and Fe–Pd Agents: Initial Mechanistic Insights. J. Med. Chem. 56, 5806–5818 (2013).

11. Fernández-Gallardo, J. et al. Organometallic Titanocene–Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties. Organometallics 33, 6669–6681 (2014).

12. Fernández-Gallardo, J. et al. Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo. 6, 5269–5283 (2015).

13. Mui, Y. F. et al. Titanocene–Gold Complexes Containing N-Heterocyclic Carbene Ligands Inhibit Growth of Prostate, Renal, and Colon Cancers in Vitro. Organometallics 35, 1218–1227 (2016).

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