Shedding light on platinum chemotherapy: a new mechanistic approach (360G-Wellcome-209173_Z_17_Z)
Despite their widespread clinical use in cancer treatment, platinum(II) complexes, including cisplatin, present critical issues such as severe side effects and onset of resistance. Furthermore, their mechanism of action is not fully understood and no reliable patient stratification tool exists. Novel prodrugs based on photoactivatable platinum(IV) complexes are reduced to cytotoxic platinum(II) species upon irradiation with visible light, providing spatial control of their cytotoxicity. Photoactivated complexes are active in cisplatin-resistant cell lines suggesting a different mechanism of action. I will investigate the mechanism of action of platinum-based anticancer drugs on- and off-target, with focus on photoactivatable complexes and clinically established drugs. The cellular targets will be identified by functional genetics experiments (RNAi/CRISPR-Cas9 screening) and the fate of platinum in vivo will be evaluated by SPECT imaging with platinum-195m labelled complexes in mouse xenograft cancer models (Goal 1). The positron-emitting isotope copper-64 will also be used to evaluate copper-transporter Ctr1 as a biomarker to predict response to platinum-based chemotherapy (Goal 2). Based on these findings, I will modify photoactivatable platinum(IV) complexes (i) to reduce their off-target toxicity by attachment to antibodies targeting specific cancer-cells receptors and (ii) to enhance cytotoxic effect upon photoactivation, by attachment to light-harvesting chromophores (Goal 3).
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Grant Details
Amount Awarded | 250000 |
Applicant Surname | Imberti |
Approval Committee | Basic Science Interview Committee |
Award Date | 2017-11-08T00:00:00+00:00 |
Financial Year | 2017/18 |
Grant Programme: Title | Sir Henry Wellcome Postdoctoral Fellowship |
Internal ID | 209173/Z/17/Z |
Lead Applicant | Dr Cinzia Imberti |
Partnership Value | 250000 |
Planned Dates: End Date | 2023-06-01T00:00:00+00:00 |
Planned Dates: Start Date | 2018-06-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | West Midlands |
Sponsor(s) | Prof Peter Sadler |