The Establishment of Lymphoma Patient-specific Human-Induced Pluripotent Stem Cells (hiPSCs) and derived-Cardiomyocytes (hiPSC-CMs) to Investigate Doxorubicin Induced-Cardiotoxicity. A cardiotoxicity disease modelling.
| Title | The Establishment of Lymphoma Patient-specific Human-Induced Pluripotent Stem Cells (hiPSCs) and derived-Cardiomyocytes (hiPSC-CMs) to Investigate Doxorubicin Induced-Cardiotoxicity. A cardiotoxicity disease modelling. |
|---|---|
| Acronym | LYMPH-CARDIOTOX |
| Start date | 2024-07-01 |
| End date | 2027-06-30 |
| Sponsor | Ministry of Health (MOH) Malaysia |
| Institution | Institute for Medical Research |
| Principal investigator | Nurul Ain Nasim Mohd Yusof
E-Mail: nurulain.my@moh.gov.my |
Associated cell lines
Project Description
Cardiovascular toxicity is a primary cause of death among cancer survivors, and it has become increasingly prevalent due to improved cancer survival rates. Among the treatments used for cancer regimes are anthracyclines. One of them is doxorubicin (DOX). Previous research has found that children are more vulnerable to the cardiotoxic effects of DOX than adults, which could be due to differences in cardiomyocyte maturity levels, although the underlying processes are unknown (Cui et al., 2019). In doxorubicin-treated lymphoma patients, it was reported an increase of fivefold in congestive heart failure, with 28% of left ventricular dysfunction after 8 years of treatment and 20% overt cardiac complications of 9 years after treatment (Hequet et al., 2004; Moser et al., 2005). The cardiotoxicity increases two to threefold in young survivors of Hodgkin’s lymphoma, a patient group with an otherwise excellent prognosis and represents the leading cause of non-malignant death in this group (Mayr & Fridrik, 2014). To our knowledge, each patient’s unique factor contributes to a different response and hence the emergence of personalising concepts for prevention and management of cardiotoxicity that arise from cancer treatment; cardio-oncology precision medicine. Therefore, it is most significant to develop a personalized approach to study cardiotoxicity in pediatric lymphoma patients who would face a lifetime cardiac impairment. Hence, here we propose to demonstrate and establish a collection of patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that can recapitulate individual (lymphoma and healthy) patient’s Doxorubicin-induced cardiotoxicity (DIC) at a single-cell level to study DIC in paediatric Lymphoma patients. The results will be useful in integrating hiPSC into cardio-oncology to allow more precise and cost-effective prediction tools for better therapy decisions before, during and after DOX cancer treatment. It is also hoped to aid pharmacological research, mechanistic toxicity studies and hence the identification of cardioprotective pathways. This project is scheduled for 3 years. Despite ongoing advances in cardio-oncology, cardiotoxicity remains one of the most serious side effects of cancer treatment. Burridge et al. only used samples from adult women with breast cancer in their investigation, it is shown that human hiPSC-CMs from patients who experienced cardiotoxicity will be more sensitive to doxorubicin than hiPSC-CMs generated from patients who did not experience it. However, it is impossible to assume that other patient groups will have the same precise biology for cardiotoxicity as this breast cancer patients’ group. As DOX-induced heart failure can appear very late after the last administration, perhaps most impactful would be the development of a personalized approach to avoid cardiotoxicity in current/former pediatric cancer patients, who would face a lifetime of cardiac disability; as such current/former pediatric lymphoma patients. Other justifications include: 1. It is not possible to predict who will develop anthracycline/ doxorubicin-induced cardiotoxicity as there is no current cellular mechanistic tools available to study or avoid ACT or DIC. 2. This project will also establishing high-quality Malaysia owned iPSCs. 3. This will be the first study in Malaysia using patient-specific hiPSC-CMs for DOX cardiotoxicity assessment to support better understanding in cardio-oncology.