Pharmacogenomics and radiogenomics

In this MRFF-funded VPCC program, we will focus on identifying individual genetic risks of patients to the toxicities of cancer treatments, including chemotherapy and radiation, by applying the research principles of pharmacogenomics and radiogenomics.

Patients who are considered at high risk of toxicity to specific chemotherapy drugs could have several options, including modifying drug dose, substituting another drug or being offered an antidote. The best example is anthracycline-induced cardiotoxicity (heart damage) for which the antidote known as dexrazoxane is approved under specific clinical circumstances.

Several projects will be the focus of initial VPCC pharmacogenomics and radiogenomics research:

Unacceptable Toxicities in Acute Lymphoblastic Leukaemia coupled with Pharmacogenomics Analysis

Whole genome sequencing from patients treated for acute lymphoblastic leukaemia (ALL) who have experienced serious adverse events considered as unacceptable toxicities will identify genetic variants linked to the risk of specific toxicities. Patients are being screened for 27 gene:drug pairs to identify high-risk metaboliser states that may predispose to toxicity. Genetic variants will then be studied in the lab towards screening drugs that can either prevent or reduce the risk.

PRIORITY-P “Randomised Control trial of pre-emptive Pharmacogenetic Screening in patients with newly diagnosed cancer or requiring bone Marrow Transplantation

This randomised control trial (funded by Kids Cancer Project) is aiming to prove a reduction of adverse drug reactions in those patients who have high-risk metaboliser states (‘actionable genotypes) according to international guidelines. The project lead by PhD Student Claire Moore will incorporate health economic analysis and extensive consumer and health practitioner informed education program.

OLAF “ Determining Adverse Drug Reaction Frequency in Paediatric Oncology Patients”

This project uses National Cancer Institute Prospective reporting of cancer therapy related symptoms (NCI-Ped-PRO-CTCAE) coupled with semi-structured academic pharmacist interviews to determine severity of symptoms (CTCAE graded) and relationship to medication exposure (Liverpool adverse drug reaction causality assessment tool)

“GO-PGx” – international Paediatric Pharmacogenetics trial

This trial will be opened at the respective children’s cancer centres located at The Royal Children’s Hospital and Monash Children’s Hospital to assess the relative risks of: (i) heart damage from anthracycline drugs; (ii) hearing loss (ototoxicity) from cisplatin chemotherapy; or (iii) reduced bone marrow function (myelosuppression) from mercaptopurine. These drugs are used to treat several types of common paediatric cancers, including ALL, various types of sarcomas and germ cell tumours. Risk reports will be reviewed by the child’s treating oncologist and there will be discussion with the family regarding whether changes to the treatment plan will be made. We will also set up consumer-led focus groups at both Melbourne-area children’s hospitals.

Radiogenomics

Children who have developed cognitive changes as a result of radiation, chemotherapy, or both will have NGS of DNA obtained from their blood to retrospectively identify those at increased risk of brain toxicity.

Children who have developed second cancers as a result of radiation will have DNA from their blood and the new cancer sequenced to identify genetic risk as well as learn more about radiation-induced cancers in children.