There is an urgent need to improve outcomes of patients with primary malignant brain tumors for which progress has been limited. At present, the 5-year survival rates for glioma patients hovers around 34% in the lower category among human malignancies. An even more gruesome picture is presented by glioblastoma that has less than 5% survival at five years, which unfortunately represents the majority of primary malignant brain tumors in adults. Recently, the discovery that mutations of isocitrate dehidrogenase 1 and 2 (IDH1,2) are found in up to 80% of different glioma types, together with data suggesting that IDH mutations are early drivers of tumorigenesis present an exciting opportunity for the development of new treatments for this disease. Many research groups and pharmaceutical companies are in very advanced phases for obtaining agents targeting mutant IDH that can be tested in human clinical trials. In this context, better imaging tools are criticalto accelerate the translation of new drugs from bench to bedside. The long-term goal is establishing new in vivo molecular imaging methods for translational research in cancer to facilitate the understanding and development of new therapies. In vivo cancer imaging is appealing especially because it can capture the entire tumor heterogeneity and it is non-invasive. In particular, the objective in this application is to image longitudinally and quantify non-invasively the levels of 2-hydroxyglutarate (2HG) in mutant IDH1 glioma patients during treatment. A key metabolic alteration in these patients is the large accumulation of the oncometabolite 2HG due to a gain of function of mutant IDH enzyme. High levels of 2HG was shown to approach 100% specificity for IDH mutations in gliomas and several other cancers with frequent IDH mutations. Hence, treatment induced changes in the activity of mutant IDH enzyme should be reflected by changes in 2HG levels. Based on the above considerations, the central hypothesis is that 2HG can be used as a prognostic and pharmacodynamic imaging biomarker to non-invasively quantify and predict treatment response in glioma patients with IDH1 mutations. Guided by strong preliminary data produced by the applicant, this hypothesis will be tested by pursuing the following two specific aims: 1) Develop and validate robust MR spectroscopic imaging (MRSI) methodology for quantifying 2HG in mutant IDH1 glioma patients; and 2) Longitudinal imaging and quantification of 2HG levels in mutant IDH1 glioma patients undergoing clinical trials targeting mutant IDH1. A strong rationale for the proposed research is that in order to assess whether candidate compounds are effectively targeting mutant IDH in glioma patients there are no other feasible alternatives than MRSI. Under the first aim, MRSI methods already proven by the applicant to unambiguously detect 2HG will be further improved to have better sensitivity and lower variability. To achieve these goals, several techniques shown by the same investigator, including adiabatic excitation, fast acquisition and real- time correction of motion artifacts and hardware drifts, will be combined with external electronic calibration for absolute quantification. Under the second aim, treatment response to drugs targeting mutant IDH1 gliomas will be determined in patients by employing these newly developed methods. The approach is innovative, because it goes beyond the current focus of diagnosing IDH1 mutations to the more practical purpose of quantifying treatment response in patients harboring this mutation. The proposed research is significant because it will determine drug action in mutant IDH1 glioma patients, and advance the understanding of the role that metabolic disturbances have in tumor initiation and maintenance. This knowledge is important to guide the development of new treatments for this subtype of gliomas, and has the potential to be applicable to other cancers where IDH1 mutations are frequent, as well as a variety of metabolic, neurological and psychiatric diseases.
The proposed research is relevant to public health because it will quantify treatment response to new therapeutic agents for primary malignant brain tumors bearing mutations of isocitrate dehydrogenase (IDH). Improved imaging methods will be created for clinical trials of patients and the gained knowledge is expected to guide the development of new therapies, and provide fundamental understanding of the biochemical pathways used by cancer cells to proliferate. Thus, the proposed research is relevant to the parts of NCI's mission that pertain to cause, diagnosis, and treatment of cancer. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the 'Critique' section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting.
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