Combination therapeutics of Nilotinib and radiation in acute lymphoblastic leukemia as an effective method against drug-resistance

Abstract

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is characterized by a very poor prognosis and a high likelihood of acquired chemo-resistance. Although tyrosine kinase inhibitor (TKI) therapy has improved clinical outcome, most ALL patients relapse following treatment with TKI due to the development of resistance. We developed an in vitro model of Nilotinib-resistant Ph+ leukemia cells to investigate whether low dose radiation (LDR) in combination with TKI therapy overcome chemo-resistance. Additionally, we developed a mathematical model, parameterized by cell viability experiments under Nilotinib treatment and LDR, to explain the cellular response to combination therapy. The addition of LDR significantly reduced drug resistance both in vitro and in computational model. Decreased expression level of phosphorylated AKT suggests that the combination treatment plays an important role in overcoming resistance through the AKT pathway. Model-predicted cellular responses to the combined therapy provide good agreement with experimental results. Augmentation of LDR and Nilotinib therapy seems to be beneficial to control Ph+ leukemia resistance and the quantitative model can determine optimal dosing schedule to enhance the effectiveness of the combination therapy.

Biophysical Characterization of the Leukemic Bone Marrow Vasculature Reveals Benefits of Neoadjuvant Low-Dose Radiation Therapy

“…52 Additionally, LDRT for hematopoietic malignancies can be explored with more traditional therapeutic agents that elicit off-target toxicity or have synergistic effects. 53,54 Although QMPM is useful to understand therapeutic delivery and microscopic vascular changes in the bone marrow, it is limited to preclinical studies only. Noninvasive macroscopic imaging such as dynamic contrastenhanced MRI will need to be used to investigate the effects of LDRT on therapeutic delivery and the BMV for clinical translation.…”

“… 52 Additionally, LDRT for hematopoietic malignancies can be explored with more traditional therapeutic agents that elicit off-target toxicity or have synergistic effects. 53 , 54 …”

New biomarkers and therapeutic strategies in acute lymphoblastic leukemias: Recent advances

“…More data are available on the combination of Nilotinib with chemotherapy in the first‐line setting, and the combination was reported to be feasible and effectively achieved high cumulative complete molecular remission and HRFS rates . Recent data showed the efficacy of this drug combined with radiation in overcoming chemo‐resistance in Ph + ALL . Nilotinib was also reported to be effective in overcoming chemoresistance in BCR‐ABL1‐like phenotype ALL .…”

Genotype patterns in growing solid tumors

“…A mathematical theory has been developed for the clonal expansion model to make predictions about the level of intratumor heterogeniety [4,14], the number of passenger (neutral) mutations in cancer cells [2,39], and more practical questions such the evolution of resistance to treatment [21,27,38], and the effectiveness of combination therapy [3,25,28]. See [12] for an introduction to the mathematics underlying many of these applications.…”