PhD Scholarship Top-up student profile: Melissa Desouza

Defining the role of tropomyosins in apoptosis

Award:  Melissa is a recipient of a two-year PhD Scholarship Top-up

Supervisor: Prof Peter Gunning, Professor of Oncology Research, School of Medical Sciences, UNSW

Tropomyosins are an integral component of the actin cytoskeleton that defines functionally distinct actin filament populations. Upon cellular transformation, the tropomyosin expression profile is dramatically altered with an increased reliance upon low molecular weight isoforms such as Tm5NM1 and decreased expression of high molecular weight isoforms such as Tm1. We have designed a novel class of anti-tropomyosin compounds that target the cancer-associated isoform Tm5NM1 and have demonstrated that our lead compound TR100 disrupts the actin cytoskeleton and effectively reduces neuroblastoma cell growth both in vitro and in vivo. It is now imperative that we determine the mechanism by which these compounds instigate cell death to further develop their chemotherapeutic potential. My project aims to determine the role of specific tropomyosin populations in apoptosis and to utilise this knowledge to determine the mechanism by which our anti-tropomyosin compounds induce tumour cell death.

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What is the translational application of your project?

The actin cytoskeleton has been a long sought-after target for the treatment of cancer due to its fundamental role in processes essential to cellular transformation, such as proliferation and migration. However, the success of actin-targeting compounds has been problematic due to indiscriminate targeting of the global actin filament population including those populations involved in the contractile unit of the heart and diaphragm. Our anti-tropomyosin compounds eliminate this unwanted side effect by targeting a sub-set of tropomyosin filaments that are expressed in tumour cells specifically. Furthermore, TR100 treatment has minimal impact on the contractile apparatus of muscle cells increasing the therapeutic potential of these compounds.

Anti-tropomyosin compounds have the capacity to treat numerous cancer cell types that show an increased reliance upon TM5NM1, such as neuroblastoma, melanoma and colon cancer. Understanding how perturbations in Tm5NM1 containing filaments initiate cell death will enable us to determine how anti-tropomyosin compounds can be integrated with existing therapies for melanoma and neuroblastoma to increase their effectiveness and improve patient outcomes (i.e. targeting two cell death pathways synergistically).

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“As a medical researcher I wish to make a difference in the lives of people suffering from cancer by contributing to the development of novel chemotherapeutics that have reduced side effects. I believe the core values of the TCRN fulfil this aspiration and that this network is intrinsic to the successful development of novel therapeutic regimes. I also believe that being part of the TCRN will enable me to network with successful researchers and clinicians that will be mentors for my future career in research.”

Melissa completed her third year of PhD studies at the School of Medical Sciences, UNSW in 2013. 

  TCRN PhD Scholarship Top-up awardee Melissa Desouza