Abnormal metabolism is a hallmark of cancer. One of the most consistently deregulated pathways in cancer is membrane metabolism, and more specifically the metabolic pathways involving choline and ethanolamine that lead to membrane build-up and breakdown. Magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) have been applied in numerous basic, preclinical, and clinical studies to detect and analyze the intermediates of abnormal membrane metabolism in many different types of cancer. The MRS-detected metabolites are choline, phosphocholine, glycerophosphocholine, as well as ethanolamine, phosphoethanolamine, and glycerophosphoethanolamine. Proton and ³¹P MRS have been applied to detect these membrane-derived metabolites in studies spanning from cells to animals to humans, with the goals of developing such MRS approaches for initial diagnosis and staging, treatment selection and monitoring, and follow-up of cancer patients. Noninvasive MRS and MRSI studies have shown promise for the use in the early assessment of treatment response in cancer patients undergoing chemotherapy or novel targeted therapies.

The network of enzymes that encompasses the build-up and breakdown pathways of choline and ethanolamine membrane metabolism has been the subject of study since the 1980ies. More recent advances are geared towards understanding the molecular biology and biochemistry of the involved enzymatic reactions in these metabolic pathways. Several studies have focused on developing treatment targets from within these metabolic pathways for MRS-guided treatment strategies. Examples of such treatment strategies are the targeting of choline kinase alpha, the phospholipases D, C, and A₂, and the glycerophosphodiesterases GDPD5 and GDPD6. Investigations into the oncogenic signaling pathways that lead to alterations in these membrane metabolic pathways have pioneered the development of MRS-detected surrogate markers of treatment response when targeting these oncogenic signaling pathways. One example of such targeting is the MRS-readout of an increased total choline or phosphocholine signal for detecting the response to histone deacetylase (HDAC) inhibitors in breast cancer models.

Overall protein metabolism is also consistently deregulated in cancer, and leads to an increased turnover of protein. This can be detected as an increased amide proton transfer (APT) contrast, which detects the presence of soluble proteins with amide protons exchanging at slow to intermediate exchange rates. APT contrast is based on chemical exchange saturation transfer (CEST) and has been detected in a variety of tumors, which showed increased APT signal as compared to surrounding healthy tissue. APT has been applied to grading brain tumors and to detecting the chemotherapy response of breast cancers in vivo, where APT increased with progressive disease and decreased with partial or complete response.

CEST is emerging as a technique that provides high sensitivity and specificity for detecting exchangeable protons in hydroxyl (-OH), amine (-NH₂), and amide (-C(O)NH-) groups in distinct molecules through transfer of signal loss between these protons and water. CEST contrast occurs when these protons exchange with water with a frequency offset that is larger than their exchange rate. As recently demonstrated, CEST imaging could potentially be a more sensitive method to monitor endogenous metabolites in cancers, because it can result in an up to several fold increase of metabolite signal, due to exchange with water. However, the detected CEST resonances are generally broader than those detected with ¹H MRS with the width of the lines also affected by the saturation field strength.

In summary, this presentation will cover current ¹H and ³¹P MRS approaches as well as CEST and APT techniques, which detect tumor membrane and protein metabolism, along with a summary of the detected molecules in the realm of cancer diagnosis and treatment monitoring.