Speakers - CRDWC 2025

Tiziana Parisi

  • Designation: CEO, CSO, and Co-founder of Paralog Therapeutics Inc.
  • Country: USA
  • Title: Exploiting evolution to target cancer

Abstract

Despite the considerable advances achieved in identifying tumor-driving mutations, the full potential of precision medicine is far from being unleashed. Existing cancer drugs allow gene function to be blocked and therefore almost exclusively target oncogenes. Opportunistic use of synthetic lethality, however, holds the prospects of expanding the realm of candidate genes to include tumor suppressors and even passenger mutations. Synthetic lethality occurs when co-inactivation of two genes leads to cell or organismal death, while deregulation of either gene alone is compatible with viability. The use of PARP inhibitors in BRAC1- or BRAC2-deficient tumors provides an exemplary application of this phenomenon in cancer therapy. As synthetic lethal genes often have similar functions, a rich source for them can be found in genes originating from duplication of a common ancestral sequence, called paralogs. Indeed, RNAi and CRISPR single or combined screens have confirmed this assumption and greatly facilitated the identification of paralogs that, when targeted as pairs, hinder cancer cell growth. As an added benefit, these tools can also be applied to find vulnerabilities associated with non-driver or passenger cancer mutations. These can occur in paralogs that undergo deletion as a collateral effect of tumor suppressor inactivation.

In summary, synthetic/paralog lethality gives us the unique opportunity to bypass the biggest impediment to targeting tumor suppressors and/or gene inactivation encountered so far: the absence of a gene product. Not surprisingly, however, this strategy also comes with challenges. Synthetic vulnerability is often context-dependent, and finding the right models and/or tools to unveil it is not straightforward. As a corollary, identifying synthetic lethal genes can be daunting even when the search is restricted to paralogs, and could result in false positives and/or negatives. Furthermore, similarities between paralogs can render targeting a single gene in the pair difficult, leading to simultaneous protein inactivation and consequent cell and/or organismal toxicity.

This talk will illustrate where the field of synthetic/paralog lethality stands and discuss the advantages and drawbacks of this approach.

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