Developing a patient specific approach to the treatment of CP-CML with tyrosine kinase inhibitors: investigating the factors which determine response to nilotinib and dasatinib.
As one of the leading international groups studying the biology and therapy of chronic myeloid leukaemia (CML), our aim is to define the optimal upfront treatment for this disease. There has been remarkable progress in the management of CML over the past decade which has resulted in it being converted from a generally fatal disease in the 1990s to a chronic disease which is usually well controlled long-term with tyrosine kinase inhibitor (TKI) therapy. Imatinib, the first TKI drug developed to target CML, results in excellent responses in 60-70% of patients with chronic phase CML (CP-CML). However a significant proportion of patients are not effectively treated with imatinib due to intolerance or resistance. More potent TKI drugs (nilotinib and dasatinib) are also now available in Australia for first-line treatment. While it is possible that one TKI drug will emerge as clearly superior therapy for all patients our recent studies suggest that it is more likely that an individualised approach to TKI therapy would be more rational and cost-effective.
Our previous studies in patients receiving imatinib have identified biomarkers that are predictive of the patients’ response to the treatment, and can be used to optimise patient-specific imatinib therapy. We now seek to broaden our studies to develop a strategy for customising front-line therapy for all CP-CML patients. These studies will initially focus on the drugs imatinib and nilotinib.
Our main objective is to identify a small number of genes (a specific genetic signature) that can be used to determine, at diagnosis, a patient's predicted response to a given therapeutic. With this information clinicians will be able to more effectively treat patients upfront with a therapy to which they are expected to respond well. This benefits not only the patient's quality of life but also the cost to local health care systems as patients are not given therapy to which they are expected to respond poorly.
What we aim to achieve
If successful this new diagnostic gene signature will allow for rapid determination, using a small amount of blood, of a patient's predicted response to a given drug. The implications of this development are many and varied. Currently techniques used to indicate a patient's response to a given therapy use large volumes of blood and are labour intensive. With this predictive gene signature developed as a kit, the process would be technically easy, take little time and require only a small amount of patient blood. This is beneficial to the patient as they will need less blood taken than is done currently and the results would be available quickly so that their clinician can decide on their therapeutic response in a timely fashion. Additionally as the current tests use radio-labelled drugs the tests are not applicable in all diagnostic labs. The development of our gene signature kit would be useable throughout all laboratories/diagnostic centres.
Our next steps and milestones
The funds from this grant were used to perform extensive genetic studies on over 120 CML patients to correlate their genetic signatures with their response to their treatments. We then used this information to determine a specific gene signature that identified patients who are predicted to respond well to a given therapeutic. Future studies will determine if this gene signature can robustly stratify these patient risk groups. Assuming this we will develop a genetic diagnostic kit.
What motivates me
I am motivated to pursue cancer research as I believe that therapies, even those considered to be good, can always be improved. When you consider a cancer patient you should not only consider the management of the disease itself but also the quality of life that you afford to this patient. For this reason I believe translational research (from bench to bedside) to be integral for improving current therapeutics for both the quality of life for the patient, as well as for improved treatment of the cancer.
My message to supporters
While CML is a chronic disease that is relatively well controlled with current therapeutics, we still face the issue of patients not responding optimally to the front line therapy they receive. The development of the novel diagnostic kit, aided by Cancer Council SA research funding, will allow patients to be identified as responding well or poorly to a given therapeutic so that clinicians can use this information to guide their therapeutic choice. The ultimate aim is that all patients receive the correct therapy upfront to improve their quality of life (i.e. will not receive a drug that will be ineffective) and subsequently result in the best therapeutic outcome.