Translation of Noninvasive Metabolic Biomarkers to Targeted Therapy for Cancer

TRANSLATION OF NONINVASIVE METABOLIC BIOMARKERS TO TARGETED THERAPY FOR CANCER PROJECT SUMMARY/ABSTRACT The genetic mutations that make a living cell become cancer produce faulty signaling cascades that alter the cell’s metabolic processes and metabolites. This metabolic reprogramming, called the Warburg effect, is present

in most cancers. It is demonstrated primarily by increased lactate formation from glucose, despite proper oxy- genation and functional mitochondria. In addition, macromolecule precursors favoring cell growth and division are also increased (e.g., alanine for protein synthesis). Notably, new cancer therapies target these faulty cas-

cades. Thus, successful treatment with these targeted therapies must modify the metabolite content in the tumor. For example, Bruton’s tyrosine kinase (BTK), hyperactive in mantle cell lymphoma (MCL), alters the B-cell receptor signaling cascade. Thus, the hyperactive BTK favors cancer processes, including the Warburg effect.

Therefore, BTK inhibition (BTKi) is a potential treatment choice for MCL. Our preclinical studies showed lactate and alanine reductions in BTKi-sensitive human MCL cell lines in cul- ture and MCL xenografts. In comparison, MCL models unresponsive to BTKi do not show these metabolic changes. Notably, these metabolic changes during effective BTKi therapy precede the objective evidence of

tumor response to therapy (i.e., reduction of viability in cultured cell lines or tumor volume in xenografts). Our overall goal is to assess the clinical translatability of our preclinical studies. Thus, our central hypothesis states that the altered tumor content of lactate and alanine in BTKi-sensitive tumors of MCL patients precede

the reduction of tumor burden, supporting their potential use as predictive biomarkers of response. However, to test our hypothesis, we aim to assess the feasibility of measuring lactate and alanine in tumors of MCL patients. Our group has helped develop and improve a robust magnetic resonance spectroscopic imaging method, the

Hadamard-selective multiple quantum coherence (Had-Sel-MQC). We adapted this method to measure lactate and alanine selectively, making it a simplified evaluation of the Warburg effect. Additionally, the Had-Sel-MQC anatomically localizes lactate and alanine, allowing their noninvasive assessment of tumors in their place in the

body (i.e., in situ). Furthermore, we have transferred the Had-Sel-MQC to clinical whole-body magnetic reso- nance imagers and recently improved it for its application to human subjects (Lee, 2022, doi: 10.1088/2057- 1976/ac57ad, and Lee, 2022, doi: 10.1016/j.mri.2022.08.020). We will study 15 healthy volunteers and 30 MCL patients in this feasibility project. Our specific goal is to

ensure that the MRSI exam achieves proper localization of tumor signals with the best spectral quality (i.e., improved B0-shimming and water and lipid suppression) irrespective of the body part studied. In addition, we will pay special attention to tumors in the torso to assess how cardiac and respiration movements affect the exam

and determine the best way to minimize their effect.