Overhauser Enhanced Magnetic Resonance Imaging (OMRI)

Division Of Basic Sciences - Nci

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Abstract

Evaluation of JG-98, inhibitor of HSP70 by metabolic MRI: The androgen receptor is a key regulator of prostate cancer and the principal target of current prostate cancer therapies collectively termed androgen deprivation therapies. Insensitivity to these drugs is a hallmark of progression to a terminal disease state termed castration-resistant prostate cancer. Therefore, novel therapeutic options that slow progression of castration-resistant prostate cancer and combine effectively with existing agents are in urgent need. We show that JG-98, an allosteric inhibitor of HSP70, re-sensitizes castration-resistant prostate cancer to androgen deprivation drugs by targeting mitochondrial HSP70 (HSPA9) to suppress aerobic respiration. Rather than impacting androgen receptor stability as previously described, JG-98's primary effect is inhibition of mitochondrial translation, leading to disruption of electron transport chain activity as shown by 13C MRI using hyperpolarized 133C labeled pyruvate. Although functionally distinct from HSPA9 inhibition, direct inhibition of the electron transport chain with a complex I or II inhibitor creates a similar physiological state capable of re-sensitizing castration-resistant prostate cancer to androgen deprivation therapies. These data identify a significant role for HspA9 in mitochondrial ribosome function and highlight an actionable metabolic vulnerability of castration-resistant prostate cancer. a-Ketoglutarate is a key biomolecule involved in a number of metabolic pathways horizontal line most notably the TCA cycle. Abnormal alpha-ketoglutarate metabolism has also been linked with cancer. Here, isotopic labeling was employed to synthesize [1-(13)C,5-(12)C,D(4)]alpha-ketoglutarate with the future goal of utilizing its [1-(13)C]-hyperpolarized state for real-time metabolic imaging of alpha-ketoglutarate analytes and its downstream metabolites in vivo. The signal amplification by reversible exchange in shield enables alignment transfer to heteronuclei (SABRE-SHEATH) hyperpolarization technique was used to create 9.7% [1-(13)C] polarization in 1 minute in this isotopologue. The efficient (13)C hyperpolarization, which utilizes parahydrogen as the source of nuclear spin order, is also supported by favorable relaxation dynamics at 0.4 muT field (the optimal polarization transfer field): the exponential (13)C polarization buildup constant T(b) is 11.0 +/- 0.4 s whereas the (13)C polarization decay constant T(1) is 18.5 +/- 0.7 s. An even higher (13)C polarization value of 17.3% was achieved using natural-abundance alpha-ketoglutarate disodium salt, with overall similar relaxation dynamics at 0.4 muT field, indicating that substrate deuteration leads only to a slight increase ( approximately 1.2-fold) in the relaxation rates for (13)C nuclei separated by three chemical bonds. Instead, the gain in polarization (natural abundance versus [1-(13)C]-labeled) is rationalized through the smaller heat capacity of the "spin bath" comprising available (13)C spins that must be hyperpolarized by the same number of parahydrogen present in each sample, in line with previous (15)N SABRE-SHEATH studies. Remarkably, the C-2 carbon was not hyperpolarized in both alpha-ketoglutarate isotopologues studied; this observation is in sharp contrast with previously reported SABRE-SHEATH pyruvate studies, indicating that the catalyst-binding dynamics of C-2 in alpha-ketoglutarate differ from that in pyruvate. We also demonstrate that (13)C spectroscopic characterization of alpha-ketoglutarate and pyruvate analytes can be performed at natural (13)C abundance with an estimated detection limit of 80 micromolar concentration x *%P(13C). All in all, the fundamental studies reported here enable a wide range of research communities with a new hyperpolarized contrast agent potentially useful for metabolic imaging of brain function, cancer, and other metabolically challenging diseases