Abstract:DCE-MRI and FDG-PET revealed loss of vessel functionality, impaired glucose delivery and reduced metabolic activity prior to cell death. [1-C]lactate-to-[C]bicarbonate ratios increased significantly during treatment, indicating a decline in respiratory activity driven by the onset of hypoxia. HPMRS is promising for early detection of metabolic stress inflicted by VDAs, which cannot easily be inferred based on blood flow measurements.
“…Our previous studies in the C3H mammary carcinoma confirm CA4P can significantly reduce tumor perfusion for extensive periods [37][38][39], and this leads to an induction of necrosis and corresponding tumor growth inhibition [37,40,41]. Although OXi4503 is an analogue of CA4P, it is superior to the parent compound [40] because it induces greater vascular damage [42] and undergoes oxidative activation to a quinine intermediate, thereby, also giving it direct cell killing properties [43]. Indeed, our own studies using this C3H mammary carcinoma clearly show OXi4503 to have a greater effect than CA4P on the induction of tumor necrosis and subsequent inhibition of tumor growth [40].…”
Immune therapy improves cancer outcomes, yet many patients do not respond. This pre-clinical study investigated whether vascular disrupting agents (VDAs) could convert an immune unresponsive tumor into a responder. CDF1 mice, with 200 mm3 C3H mammary carcinomas in the right rear foot, were intraperitoneally injected with combretastatin A-4 phosphate (CA4P), its A-1 analogue OXi4503, and/or checkpoint inhibitors (anti-PD-1, PD-L1, or CTLA-4 antibodies), administered twice weekly for two weeks. Using the endpoint of tumor growth time (TGT5; time to reach five times the starting volume), we found that none of the checkpoint inhibitors (10 mg/kg) had any effect on TGT5 compared to untreated controls. However, CA4P (100 mg/kg) or OXi4503 (5–50 mg/kg) did significantly increase TGT5. This further significantly increased by combining the VDAs with checkpoint inhibitors, but was dependent on the VDA, drug dose, and inhibitor. For CA4P, a significant increase was found when CA4P (100 mg/kg) was combined with anti-PD-L1, but not with the other two checkpoint inhibitors. With OXi4503 (50 mg/kg), a significant enhancement occurred when combined with anti-PD-L1 or anti-CTLA-4, but not anti-PD-1. We observed no significant improvement with lower OXi4503 doses (5–25 mg/kg) and anti-CTLA-4, although 30% of tumors were controlled at the 25 mg/kg dose. Histological assessment of CD4/CD8 expression actually showed decreased levels up to 10 days after treatment with OXi4503 (50 mg/kg). Thus, the non-immunogenic C3H mammary carcinoma was unresponsive to checkpoint inhibitors, but became responsive in mice treated with VDAs, although the mechanism remains unclear.
“…Our previous studies in the C3H mammary carcinoma confirm CA4P can significantly reduce tumor perfusion for extensive periods [37][38][39], and this leads to an induction of necrosis and corresponding tumor growth inhibition [37,40,41]. Although OXi4503 is an analogue of CA4P, it is superior to the parent compound [40] because it induces greater vascular damage [42] and undergoes oxidative activation to a quinine intermediate, thereby, also giving it direct cell killing properties [43]. Indeed, our own studies using this C3H mammary carcinoma clearly show OXi4503 to have a greater effect than CA4P on the induction of tumor necrosis and subsequent inhibition of tumor growth [40].…”
Immune therapy improves cancer outcomes, yet many patients do not respond. This pre-clinical study investigated whether vascular disrupting agents (VDAs) could convert an immune unresponsive tumor into a responder. CDF1 mice, with 200 mm3 C3H mammary carcinomas in the right rear foot, were intraperitoneally injected with combretastatin A-4 phosphate (CA4P), its A-1 analogue OXi4503, and/or checkpoint inhibitors (anti-PD-1, PD-L1, or CTLA-4 antibodies), administered twice weekly for two weeks. Using the endpoint of tumor growth time (TGT5; time to reach five times the starting volume), we found that none of the checkpoint inhibitors (10 mg/kg) had any effect on TGT5 compared to untreated controls. However, CA4P (100 mg/kg) or OXi4503 (5–50 mg/kg) did significantly increase TGT5. This further significantly increased by combining the VDAs with checkpoint inhibitors, but was dependent on the VDA, drug dose, and inhibitor. For CA4P, a significant increase was found when CA4P (100 mg/kg) was combined with anti-PD-L1, but not with the other two checkpoint inhibitors. With OXi4503 (50 mg/kg), a significant enhancement occurred when combined with anti-PD-L1 or anti-CTLA-4, but not anti-PD-1. We observed no significant improvement with lower OXi4503 doses (5–25 mg/kg) and anti-CTLA-4, although 30% of tumors were controlled at the 25 mg/kg dose. Histological assessment of CD4/CD8 expression actually showed decreased levels up to 10 days after treatment with OXi4503 (50 mg/kg). Thus, the non-immunogenic C3H mammary carcinoma was unresponsive to checkpoint inhibitors, but became responsive in mice treated with VDAs, although the mechanism remains unclear.
“…Thus, in the case of therapeutic drugs working through this anti‐angiogenic pathway, Lac/Pyr or k PL would not be an adequate biomarker of therapeutic success and other strategies may be required to asses it. In this respect, both Park et al and Iversen et al point to a different ratio, hyperpolarized Lac/bicarbonate, as a better sensor of response to antiangiogenic agents (Supplementary Figure 4). Take home messages .…”
Section: Mrs(i)‐detectable Metabolic Hallmarks Of Cancer: Applicationmentioning
confidence: 94%
“…Four recent reports have investigated the Lac/Pyr ratio (or k PL ). Ravoori et al and Tee et al found that this ratio increases, whereas Park et al and Iversen et al found it to remain stable, when a variety of preclinical tumours (glioma, mammary carcinoma, ovarian, lung carcinoma) respond to therapy. In References 33, 35 and 36, the therapeutic agent used displayed anti‐angiogenic or vascular disrupting activity, while in Reference the drug used was an activator of PKM2.…”
Section: Mrs(i)‐detectable Metabolic Hallmarks Of Cancer: Applicationmentioning
confidence: 99%
“…Ravoori et al and Tee et al found that this ratio increases, whereas Park et al and Iversen et al found it to remain stable, when a variety of preclinical tumours (glioma, mammary carcinoma, ovarian, lung carcinoma) respond to therapy. In References 33, 35 and 36, the therapeutic agent used displayed anti‐angiogenic or vascular disrupting activity, while in Reference the drug used was an activator of PKM2. The rationale to explain this initially conflicting evidence is essentially put forward in References 33 and 36: anti‐angiogenic agents will produce hypoxic regions in the tumour, causing increased glycolytic flow to maintain required ATP (adenosine triphosphate) production by the tumour cell, overriding the decreased demand of carbon precursors for cell duplication by the growth‐arrested tumour cells.…”
Section: Mrs(i)‐detectable Metabolic Hallmarks Of Cancer: Applicationmentioning
confidence: 99%
“…In References 33, 35 and 36, the therapeutic agent used displayed anti‐angiogenic or vascular disrupting activity, while in Reference the drug used was an activator of PKM2. The rationale to explain this initially conflicting evidence is essentially put forward in References 33 and 36: anti‐angiogenic agents will produce hypoxic regions in the tumour, causing increased glycolytic flow to maintain required ATP (adenosine triphosphate) production by the tumour cell, overriding the decreased demand of carbon precursors for cell duplication by the growth‐arrested tumour cells. Thus, in the case of therapeutic drugs working through this anti‐angiogenic pathway, Lac/Pyr or k PL would not be an adequate biomarker of therapeutic success and other strategies may be required to asses it.…”
Section: Mrs(i)‐detectable Metabolic Hallmarks Of Cancer: Applicationmentioning
The contribution of MRS(I) to the in vivo evaluation of cancer-metabolism-derived metrics, mostly since 2016, is reviewed here. Increased carbon consumption by tumour cells, which are highly glycolytic, is now being sampled by 13 C magnetic resonance spectroscopic imaging (MRSI) following the injection of hyperpolarized [1-13 C] pyruvate (Pyr). Hot-spots of, mostly, increased lactate dehydrogenase activity or flow between Pyr and lactate (Lac) have been seen with cancer progression in prostate (preclinical and in humans), brain and pancreas (both preclinical) tumours. Therapy response is usually signalled by decreased Lac/Pyr 13 C-labelled ratio with respect to untreated or nonresponding tumour. For therapeutic agents inducing tumour hypoxia, the 13 C-labelled Lac/bicarbonate ratio may be a better metric than the Lac/Pyr ratio. 31 P MRSI may sample intracellular pH changes from brain tumours (acidification upon antiangiogenic treatment, basification at fast proliferation and relapse). The steady state tumour metabolome pattern is still in use for cancer evaluation. Metrics used for this range from quantification of single oncometabolites (such as 2-hydroxyglutarate in mutant IDH1 glial brain tumours) to selected metabolite ratios (such as total choline to N-acetylaspartate (plain ratio or CNI index)) or the whole 1 H MRSI(I) pattern through pattern recognition analysis. These approaches have been applied to address different questions such as tumour subtype definition, following/predicting the response to therapy or defining better resection or radiosurgery limits.
KEYWORDSanimal model study, cancer, cellular and molecular cancer imaging, hyperpolarized C-13, MRS and MRSI methods, phosphorus MRS/MRSI
| TEMPORAL AND THEMATIC BOUNDARIES OF THE TOPICS COVEREDThe authors of this review declare at the outset that there is no intention of being exhaustive or systematic. The temporal boundaries reviewed will be modest: only relevant literature since 2016, chosen according to our bias. Earlier work or reviews will only be referred to in order to put recent findings in due perspective. Authors hope that this summary will give readers a picture of how far cancer metabolism analysis with MRS(I) has advanced and, perhaps, why it is not advancing further.For quite a long time MRS, rather than MRI, has been the only approach able to evaluate cancer metabolism. Nevertheless, the MRI-derived information related to cancer metabolism should not be forgotten: consider for example the chemical exchange saturation transfer (CEST) effect caused by exchangeable protons in water-derived images of glucose uptake and metabolism in tumours. 1,2 However, apart from these CESTrelated studies, we should acknowledge that most information about cancer metabolism using MR still refers to MRS(I) acquisitions, which are the ones dealt with in our text.Supplementary Figure 1 shows a PUBMED search illustrating the different proportions of articles investigating several cancer types through MRS(I) approaches. The retrieved information can help unders...
Due to the implication of altered metabolism in a large spectrum of tissue function and disease, assessment of metabolic processes becomes essential in managing health. In this regard, imaging can play a critical role in allowing observation of biochemical and physiological processes. Nuclear imaging methods, in particular positron emission tomography, have been widely employed for imaging metabolism but are mainly limited by the use of ionizing radiation and the sensing of only one parameter at each scanning session. Observations in healthy individuals or longitudinal studies of disease could markedly benefit from non-ionizing, multi-parameter imaging methods. We therefore focus this review on progress with the non-ionizing radiation methods of MRI, hyperpolarized magnetic resonance and magnetic resonance spectroscopy, chemical exchange saturation transfer, and emerging optoacoustic (photoacoustic) imaging. We also briefly discuss the role of nuclear and optical imaging methods for research and clinical protocols.
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