Date of Award

Winter 2017

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Darren Griffith

Funder/Sponsor

Science Foundation Ireland

Keywords

Colorectal Neoplasms, Drug Therapy

Abstract

Colorectal cancer represents a major rapidly growing global challenge and a disease that warrants the need for extensive research into it’s prevention, diagnosis and treatment. Late stage colorectal cancer is typically treated with surgery and adjuvant chemotherapy. The FOLFOX chemotherapeutic regimen which comprises the Ptbased drug oxaliplatin is the current gold standard worldwide. However, despite the undisputed success of Pt-based chemotherapeutics, deleterious side effects and drug resistance are the ever present major obstacles to effective colorectal cancer treatment. Thus, there remains a constant need to develop novel therapeutic strategies. In an effort to circumvent the mechanisms that give rise to drug resistance, and to mitigate other undesired side-effects, thousands of Pt based compounds have been developed to date that conform to and deviate from the classical cis-PtA2X2 structure of clinically approved Pt drugs. Lloyd Kelland in his Nature Reviews Cancer article titled “The resurgence of platinum-based cancer chemotherapy” stated that “four major strategies can now be proposed to circumvent platinum-drug resistance in cancer patients: first, new, improved platinum drugs; second, improved delivery of platinum to tumours; third, co-administration of platinum drugs with pharmacological modulators of resistance mechanisms; and fourth, combining platinum drugs with new molecularly targeted drugs”.

Chapter 1 provides an introduction into the role of Pt-based drugs as anticancer agents, including ‘classical’ Pt drugs that are currently in use in the clinic, and a number of unconventional compounds currently under development. The remainder of Chapter 1 is split into three parts where part I reviews the function of heat shock proteins and highlights their role in cancer progression and survival, part II considers the role of cell penetrating peptides and how they can be exploited for use in cancer treatment, and part III details the hedgehog signaling pathway and it’s role in colorectal cancer development and resistance.

Heat shock protein 70 is overexpressed in colorectal cancer, playing an integral role in tumour progression and survival. In addition, this overexpression is not typically displayed in healthy non-transformed cells, and so in line with many other groups HSP70 has been recognised as a legitimate target for anticancer exploitation. Chapter 3 focuses on the synthesis, derivatisation, in silico docking and in vitro evaluation of PES, a bioactive small molecule which has been identified as a potent HSP70 inhibitor.

Cell penetrating peptides offer an exciting and legitimate strategy for use in anticancer drug delivery. Additionally, homing devices offer a highly promising strategy for active targeting. Chapter 4 details the synthesis of TPP, a 14-mer homing peptide identified to specifically target membrane bound HSP70 found on the surface of cancer cells. In addition, the synthetic approach to a number of oxaliplatin-TPP conjugates is detailed, as well identification of memHSP70+ colorectal cancer cell lines and the activity of Pt-peptide conjugates in vitro.

Hedgehog signalling is strongly associated with colon carcinogenesis and tumour growth. In addition, and significantly, this pathway is also implicated in the maintenance and differentiation of colonic cancer stem cells which are believed to be responsible for disease progression, metastasis and resistance. Hence, hedgehog signalling activity provides a genuine anticancer target. Thus, chapter 5 details a novel strategy to target colorectal cancer which incorporates the known anticancer capabilities of Pt based compounds in conjunction with a hedgehog inhibiting molecule GANT-61. Chapter 5 describes the synthesis of a number of Pt(II) and Pt(IV) complexes which comprise the Hedgehog pathway inhibitor GANT-61, an evaluation of their activity in vitro and DNA binding studies.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

7.26 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2017.

Available for download on Friday, November 30, 2018

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