Pancreatic ductal adenocarcinomas (PDACs) form hypovascular and hypoxic tumors, which are difficult to treat with current chemotherapy regimens. Gemcitabine (GEM) is often used as a first-line ...treatment for PDACs but has issues with chemoresistance and penetration in the interior of the tumor. Evofosfamide, a hypoxia-activated prodrug, has been shown to be effective in combination with GEM, although the mechanism of each drug on the other has not been established. We used mouse xenografts from two cell lines (MIA Paca-2 and SU.86.86) with different tumor microenvironmental characteristics to probe the action of each drug on the other.
GEM treatment enhanced survival times in mice with SU.86.86 leg xenografts (hazard ratio HR = 0.35,
= 0.03) but had no effect on MIA Paca-2 mice (HR = 0.91, 95% confidence interval = 0.37-2.25,
= 0.84). Conversely, evofosfamide did not improve survival times in SU.86.86 mice to a statistically significant degree (HR = 0.57,
= 0.22). Electron paramagnetic resonance imaging showed that oxygenation worsened in MIA Paca-2 tumors when treated with GEM, providing a direct mechanism for the activation of the hypoxia-activated prodrug evofosfamide by GEM. Sublethal amounts of either treatment enhanced the toxicity of other treatment
in SU.86.86 but not in MIA Paca-2. By the biomarker γH2AX, combination treatment increased the number of double-stranded DNA lesions
for SU.86.86 but not MIA Paca-2.
The synergy between GEM and evofosfamide appears to stem from the dual action of GEMs effect on tumor vasculature and inhibition by GEM of the homologous recombination DNA repair process.
39, 432-444.
Metabolic reprogramming in prostate cancer Ahmad, Fahim; Cherukuri, Murali Krishna; Choyke, Peter L
British journal of cancer,
10/2021, Letnik:
125, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Although low risk localised prostate cancer has an excellent prognosis owing to effective treatments, such as surgery, radiation, cryosurgery and hormone therapy, metastatic prostate cancer remains ...incurable. Existing therapeutic regimens prolong life; however, they are beset by problems of resistance, resulting in poor outcomes. Treatment resistance arises primarily from tumour heterogeneity, altered genetic signatures and metabolic reprogramming, all of which enable the tumour to serially adapt to drugs during the course of treatment. In this review, we focus on alterations in the metabolism of prostate cancer, including genetic signatures and molecular pathways associated with metabolic reprogramming. Advances in our understanding of prostate cancer metabolism might help to explain many of the adaptive responses that are induced by therapy, which might, in turn, lead to the attainment of more durable therapeutic responses.
Abstract Purpose Electron paramagnetic resonance (EPR) imaging has evolved as a promising tool to provide non-invasive assessment of tissue oxygenation levels. Due to the extremely short T2 ...relaxation time of electrons, single point imaging (SPI) is used in EPRI, limiting achievable spatial and temporal resolution. This presents a problem when attempting to measure changes in hypoxic state. In order to capture oxygen variation in hypoxic tissues and localize cycling hypoxia regions, an accelerated EPRI imaging method with minimal loss of information is needed. Methods We present an image acceleration technique, partial Fourier compressed sensing (PFCS), that combines compressed sensing (CS) and partial Fourier reconstruction. PFCS augments the original CS equation using conjugate symmetry information for missing measurements. To further improve image quality in order to reconstruct low-resolution EPRI images, a projection onto convex sets (POCS)-based phase map and a spherical-sampling mask are used in the reconstruction process. The PFCS technique was used in phantoms and in vivo SCC7 tumor mice to evaluate image quality and accuracy in estimating O2 concentration. Results In both phantom and in vivo experiments, PFCS demonstrated the ability to reconstruct images more accurately with at least a 4-fold acceleration compared to traditional CS. Meanwhile, PFCS is able to better preserve the distinct spatial pattern in a phantom with a spatial resolution of 0.6 mm. On phantoms containing Oxo63 solution with different oxygen concentrations, PFCS reconstructed linewidth maps that were discriminative of different O2 concentrations. Moreover, PFCS reconstruction of partially sampled data provided a better discrimination of hypoxic and oxygenated regions in a leg tumor compared to traditional CS reconstructed images. Conclusions EPR images with an acceleration factor of four is feasible using PFCS with reasonable assessment of tissue oxygenation. The technique can greatly enhance EPR applications and improve our understanding cycling hypoxia. Moreover this technique can be easily extended to various MRI applications.
The Cancer Imaging Program of the National Cancer Institute convened a workshop to assess the current status of hypoxia imaging, to assess what is known about the biology of hypoxia as it relates to ...cancer and cancer therapy, and to define clinical scenarios in which in vivo hypoxia imaging could prove valuable.
Hypoxia, or low oxygenation, has emerged as an important factor in tumor biology and response to cancer treatment. It has been correlated with angiogenesis, tumor aggressiveness, local recurrence, and metastasis, and it appears to be a prognostic factor for several cancers, including those of the cervix, head and neck, prostate, pancreas, and brain. The relationship between tumor oxygenation and response to radiation therapy has been well established, but hypoxia also affects and is affected by some chemotherapeutic agents. Although hypoxia is an important aspect of tumor physiology and response to treatment, the lack of simple and efficient methods to measure and image oxygenation hampers further understanding and limits their prognostic usefulness. There is no gold standard for measuring hypoxia; Eppendorf measurement of pO(2) has been used, but this method is invasive. Recent studies have focused on molecular markers of hypoxia, such as hypoxia inducible factor 1 (HIF-1) and carbonic anhydrase isozyme IX (CA-IX), and on developing noninvasive imaging techniques.
This workshop yielded recommendations on using hypoxia measurement to identify patients who would respond best to radiation therapy, which would improve treatment planning. This represents a narrow focus, as hypoxia measurement might also prove useful in drug development and in increasing our understanding of tumor biology.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mutant isocitrate dehydrogenase (IDHmut) catalyzes 2-hydroxyglutarate (2HG) production and is considered a therapeutic target for IDHmut tumors. However, response is mostly associated with inhibition ...of tumor growth. Response assessment via anatomic imaging is therefore challenging. Our goal was to directly detect IDHmut inhibition using a new hyperpolarized (HP)
C magnetic resonance spectroscopy-based approach to noninvasively assess α-ketoglutarate (αKG) metabolism to 2HG and glutamate.
We studied IDHmut-expressing normal human astrocyte (NHAIDH1mut) cells and rats with BT257 tumors, and assessed response to the IDHmut inhibitor BAY-1436032 (
≥ 4). We developed a new
C Echo Planar Spectroscopic Imaging sequence with an optimized RF pulse to monitor the fate of HP 1-
CαKG and 5-
C,1-
CαKG with a 2.5 × 2.5 × 8 mm
spatial resolution.
Cell studies confirmed that BAY-1436032-treatment leads to a drop in HP 2HG and an increase in HP glutamate detectable with both HP substrates. Data using HP 5-
C,1-
CαKG also demonstrated that its conversion to 2HG is detectable without the proximal 1.1% natural abundance 5-
CαKG signal. In vivo studies showed that glutamate is produced in normal brains but no 2HG is detectable. In tumor-bearing rats, we detected the production of both 2HG and glutamate, and BAY-1436032-treatment led to a drop in 2HG and an increase in glutamate. Using HP 5-
C,1-
CαKG we detected metabolism with an signal-to-noise ratio of 23 for 2HG and 17 for glutamate.
Our findings point to the clinical potential of HP αKG, which recently received FDA investigational new drug approval for research, for noninvasive localized imaging of IDHmut status.
Abstract
Background
Early detection of increased aggressiveness of brain tumors is a major challenge in the field of neuro-oncology because of the inability of traditional imaging to uncover it. ...Isocitrate dehydrogenase (IDH)-mutant gliomas represent an ideal model system to study the molecular mechanisms associated with tumorigenicity because they appear indolent and non-glycolytic initially, but eventually a subset progresses toward secondary glioblastoma with a Warburg-like phenotype. The mechanisms and molecular features associated with this transformation are poorly understood.
Methods
We employed model systems for IDH1 mutant (IDH1mut) gliomas with different growth and proliferation rates in vivo and in vitro. We described the metabolome, transcriptome, and epigenome of these models in order to understand the link between their metabolism and the tumor biology. To verify whether this metabolic reprogramming occurs in the clinic, we analyzed data from The Cancer Genome Atlas.
Results
We reveal that the aggressive glioma models have lost DNA methylation in the promoters of glycolytic enzymes, especially lactate dehydrogenase A (LDHA), and have increased mRNA and metabolite levels compared with the indolent model. We find that the acquisition of the high glycolytic phenotype occurs at the glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP)-high molecular subtype in patients and is associated with the worst outcome.
Conclusion
We propose very early monitoring of lactate levels as a biomarker of metabolic reprogramming and tumor aggressiveness.
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