Geraldine Laven-Law

The Dame Roma Mitchell Cancer Research Laboratories (DRMCRL) have an international reputation for research into sex hormone action in hormone-dependent cancers, with a particular emphasis on breast and prostate cancers.

This world-class cancer research centre brings together expertise spanning more than 30 years in basic and translational prostate and breast cancer research. It is the leading centre in Australia with a multidisciplinary team of scientists, clinicians and patient advocates dedicated to understanding how sex hormones and their receptors control tumour behaviour in both disease contexts. The information is used to understand mechanisms of resistance to existing hormonal therapies for breast and prostate cancer and in developing new strategies for disease treatment and management. Research programs span discovery, drug development and clinical translation.

A major research focus at the DRMCRL is the development of novel androgen receptor (AR) and progesterone receptor (PR) targeted therapies for breast and prostate cancer. In prostate cancer, this involves the generation of drugs to inhibit aberrant forms of the AR that drive the disease and are unresponsive to conventional androgen deprivation therapies. In the case of breast cancer, our research has led to new strategies to activate the AR or PR to inhibit growth of tumours that are driven by the estrogen receptor (ER), as well as interrogation of Selective Androgen Receptor Modulators (SARMs), which have the ability to reprogram oncogenic AR activation in ER negative breast cancer.

Our laboratory has pioneered integration of genomic technologies with unique preclinical models of human breast and prostate cancers, especially patient-derived explant cultures and xenograft models, to better understand disease mechanisms and facilitate translation of breast and prostate cancer research into the clinic.

We publish in high impact journals such as Nature, Nature Genetics, Nature Reviews Cancer, Cancer Research, Clinical Cancer Research and Oncogene. Our research is well supported by funding from nationally and internationally competitive grants. The DRMCRL offers students a wide array of projects that span cutting-edge biomedical research using contemporary pre-clinical models, genome-wide technologies and access to large proteomic/genomic databases.

We are currently actively seeking students interested in bioinformatics to interrogate these databases, with opportunities of cross faculty supervision in fields such as mathematics and machine learning.

Key Research Projects Available for DRMCRL

Project 1 - Transforming endocrine therapy for breast and prostate cancer

Description -  Breast and prostate cancers are diseases driven by abnormal sex hormone receptor activity mediated by the estrogen receptor (ER) in breast and the androgen receptor (AR) in prostate cancers. Surgery and radiation therapy for these diseases work well when the tumour is confined within the organ of origin. However, for cancers that have spread out of the breast or prostate, either locally or to other parts of the body, the major treatment strategy is to completely abolish the activity of the offending sex hormone receptor. This treatment strategy is called hormone deprivation therapy and has been employed for the past century. Overwhelming evidence indicates that hormone deprivation therapy has run its course in providing a survival advantage to people with breast or prostate cancer.

Our hypothesis is that reprogramming estrogen or androgen receptors (ER and AR) away from oncogenic activity toward more benign activity will transform endocrine therapy for breast and prostate cancer. In this project we aim to discover optimal strategies to reprogram ER or AR activity in breast and prostate cancer by investigating three complementary approaches to reprogramming ER/AR: 1) Activate other nuclear receptors that directly inhibit ER/AR signalling; 2) Utilize selective ER/AR ligands; and 3) Enhance ER/AR reprogramming with epigenetic drugs. We will then validate optimal reprogramming strategies in patient-derived xenograft “clinical trials” and clinical samples.

Available for: Honours and HDR

Start Date: Semester 1 and 2 2022 

Project 2 - Selective activation of androgen receptor to treat estrogen receptor positive breast cancer

Description - Androgens, acting via the androgen receptor (AR), a protein related to the estrogen receptor (ER), are natural inhibitors of estrogen-stimulated breast cancer growth. Although androgens are commonly considered to be male hormones, females produce androgens throughout their life. AR typically is present in the same cells as ER, resulting in estrogen and androgen hormones exerting opposing forces on the growth of ER-positive breast cancers, with estrogen having growth promoting and androgens protective effects.

The goals of this project are: 1) Investigate how stimulation of the androgen receptor (AR) by a synthetic androgen which has been shown to be well tolerated by women, inhibits the growth of estrogen-sensitive breast tumours; and 2)  Develop and evaluate proteins identified as being potential biomarkers of response to androgenic therapies.

Available for: Honours and HDR

Start Date: Semester 1 and 2 2022

Project 3 -  The clinical significance of sex hormone crosstalk in estrogen receptor positive breast cancer

Description - Breast cancer is mainly a disease in which the sex hormone estrogen stimulates uncontrolled growth via the estrogen receptor (ER). We have recently discovered that other sex hormones, including progesterone and androgen, can redirect the actions of estrogen in breast cancers to halt growth or make a tumour disappear. This project will examine the complex interaction between all three sex hormones to develop new, more effective strategies for treating breast cancer.

In this project, we will investigate the three-way interplay between ER, PR (progesterone receptor) and AR (androgen receptor) in contemporary models of breast cancer including patient derived xenografts and ex-vivo cultured primary tumour tissues. The ultimate goal is to determine clinical scenarios in which PR, AR or both could be optimally therapeutically targeted to treat ER+ breast cancer, particularly disease resistant to current ER targeting drugs.

Available for: Honours and HDR

Start Date: Semester 1 and 2 2022

Project 4 - Pushing AR toward better outcomes in breast and prostate cancers

Description - This project will establish the efficacy of drugs called SARMs (selective androgen receptor modulators) for re-activating the normal, non-oncogenic function of the AR (androgen receptor) in human-derived pre-clinical models and clinical samples of breast and prostate cancers. Currently available SARMs (eg Enobosarm) have excellent safety profiles, and are poised for rapid implementation into clinical trials. Through our collaborations with clinicians that currently run breast cancer and prostate cancer clinical trials, we have access to breast cancer and prostate cancer samples, and also an avenue to prepare them to quickly implement novel treatment strategies that arise from this project.

The aims of this project are: 1) Identify SARMs that reprogram AR from oncogenic to benign genomic loci in breast cancers and prostate cancers; 2) Identify proteins that mediate AR reprogramming in breast and prostate cancers; 3) Pre-clinically test selected SARMs with therapeutic potential; and 4) Determine the clinical scope for SARMs and candidate biomarkers derived during the project. 

Available for: Honours and HDR

Start Date: Semester 1 and 2 2022

Project 5 - Targeting CDK9 in triple negative and endocrine-resistant breast cancers

Description - Triple negative breast cancer (TNBC) is the worst form of breast cancer at diagnosis. Better treatments for these cancers is a critical unmet need. TNBC preferentially afflicts young women and those with mutations of the BRCA1 gene. Another very aggressive form of breast cancer is estrogen receptor (ER) driven cancer that becomes resistant to ER targeting therapies. Chemotherapy and more recently, CDK4/6 inhibitors are the only approved means of treating these cancers, but survival rates remain low.

This project focuses on these highly aggressive breast cancers that collectively cause the majority of breast cancer-related death.  Such cancers have phenomenal rates of growth, in part due to elevated transcriptional activation of oncogenes. In collaboration with a medicinal chemist (Prof Shudong Wang), we are testing new drugs that specifically target CDK9, a factor that can ramp up the transcriptional activity of RNA polymerase II.  The goals of this project are: 1) Demonstrate the efficacy of novel CDK9 inhibitors in a unique suite of patient-derived xenograft models of triple negative and endocrine-resistant breast cancer; 2) Identify cellular mediators of CDK9-targeted therapy in these disease subtypes; and 3) Test our CDK9 inhibitors in prospectively-collected patient derived explant tumours cultured ex vivo and evaluate a biomarker signature of treatment response.

Available for: Honours and HDR

Start Date: Semester 1 and 2 2022