Pharmaceutical Development of Innovative "Trojan Horse" Anti-Cancer Agents that Inhibit Desmoplasia by Reprogramming Signalling

THE NEW IDEA: First-In-Field "Trojan Horse" anti-cancer agents (the PPPT series) that reprogram bi-directional, oncogenic Sonic Hedgehog (SHH) signalling to inhibit desmoplasia (fibrotic "shell" formation), which stubbornly prevents permeation of standard anti-cancer drugs into the tumour

These new agents show marked and selective anti-tumour efficacy via a lipophilic “Trojan Horse” mechanism that effectively permeates tumour cells, but potentially also the fibrous desmoplasia that shields tumours from chemotherapy, to then liberate the active drug

These agents were derived from 1st & 2nd generations (GENs) of novel and safe anti-cancer agents developed by CIA and CIB from “bench to bedside.” Indeed, our 2nd GEN agent, DpC, entered multi-centre, Phase I clinical trials (NCT02688101).

Intriguingly, our 2021 studies (FASEB J. 2021;35:e21347) discovered for the 1st time that DpC uniquely reprogrammed SHH bidirectional signalling from cancer cells to stromal cells to inhibit desmoplasia by up-regulating the metastasis suppressor, NDRG1

To apply: Contact Prof Des Richardson with your CV at d.richardson@griffith.edu.au

TARGETING THE MAJOR KILLERS IN CANCER: METASTASIS AND DRUG RESISTANCE

The spread of cancer (metastasis) accounts for 90% of cancer deaths. Critically, this belligerent disease is highly resistant to conventional therapies, and new molecular targets and therapeutic avenues are urgently needed. Professor Richardson discovered innovative anti-cancer drugs that can increase the expression of a metastasis suppressor protein, NDRG1, that prevents tumour cell spread (Fig. 1). He also discovered these same drugs overcome resistance of cancers to chemotherapies by overcoming the drug efflux pump, P-glycoprotein. This project will involve examining the functions of NDRG1 and its targeting by our novel drugs to elucidate the molecular mechanisms involved in their anti-tumour activity. A range of state-of-the-art techniques will be used to maximise student training, including: tissue culture, western blot analysis, immunohistochemistry, medicinal chemistry, and confocal microscopy

Primary supervisor: Prof Des Richardson

Other supervisor: Dr. Mahendiran Dharmasivam

To apply: Contact Prof Des Richardson with your CV at d.richardson@griffith.edu.au

HARNESSING THE POWER OF THE MACROPHAGE: INNOVATIVE ANTI-CANCER DRUGS KNOWN AS 'MACA-ATTACKERS

Despite the massive potential of pharmacologically harnessing the power of the macrophage (MØ), a lack of understanding basic molecular mechanisms led to a distinct absence of MØ-based anti-cancer therapies. MØs are powerful orchestrators of the response to tumours, making up to 50% of tumour mass. The MØ powerfully exerts tumour inhibition via either cytotoxic M1-MØs, or tumour promotion via the M2-MØ phenotype. However, a unifying model of how this occurs via nitric oxide (NO) has never been elucidated. Using our expertise in exploiting transporter pharmacology to develop innovative drugs from bench-to-bedside, we will assess the transporter, multidrug resistance-associated protein 1 (MRP1), to exploit NO transport between MØs and tumour cells (Figure 2) to develop  frontier drugs  (“MACA-ATTACKERS”) to harness the immense power of the MØ.

Primary supervisor: Prof Des Richardson

Other supervisor: Dr. Mahendiran Dharmasivam

To apply: Contact Prof Des Richardson with your CV at d.richardson@griffith.edu.au

PARKINSON’S DISEASE: ALTERATIONS IN IRON AND REDOX BIOLOGY AS A KEY TO UNLOCK THERAPEUTIC STRATEGIES

Parkinson’s disease is the second most common severe neurodegenerative condition with a projected prevalence of 7.1 million people by 2025. The problem of PD is increasing in industrialized countries as the average lifespan rises, affecting 1% of those greater than 60 years old. There is impressive evidence that the metabolism of iron is disturbed in PD, with the resulting oxidative stress playing a potential role in the death of critical dopaminergic neurons in the midbrain.

THE BIG QUESTION IN PARKINSON’S DISEASE: A central question in Parkinson’s disease research is why do substantia nigra pars compacta neurons which represent 0.0001% of the total neurons in the brain demonstrate specific and high sensitivity to multiple stress stimuli? This leads to TOXIC iron loading and death of these neurons, which is key to the pathology of the disease. Why does this occur in only one exceedingly rare subset of neurons?

THE BIG ANSWER: The strikingly unique activity of dopaminergic substantia nigra pars compacta neurons is that they demonstrate autonomic pacemaking (ability to generate their own electrical spiking without synaptic input that is essential for dopamine release). This process requires the activity of L-type Calcium channels that require intense ATP generation. These data have led to the hypothesis in our laboratories of how the toxic iron overload in Parkinson’s disease causes neurodegeneration. That is, these L-type Calcium channels may not only take up calcium which is required for ATP production, but also, inadvertently iron and other metals. This iron uptake could be unregulated and lead to death of these very special neurons, as iron loading is toxic! The project will examine the role and regulation of the L-type Calcium channels in iron uptake and develop novel pharmacological treatments that remove the iron and prevent the disease.