Researchers at the University of Cincinnati have tested a new combination therapy in animal models to see if they could find a way to make an already effective treatment even better.
Since they’re using a Food and Drug Administration-approved drug to do it, this could help humans sooner than later.
These findings are published in the journal Cancer Letters.
Christina Wicker, Ph.D., a postdoctoral fellow in the lab of Vinita Takiar, MD, Ph.D., led this research which she says will hopefully extend the lives of patients one day.
“Head and neck cancer, like any cancer, is truly life-altering,” she says. “Head and neck cancer could impact your throat, tongue or nose, and patients often can’t swallow, talk or eat; it truly takes away some of the most social, enjoyable parts of life.”
Researchers in this study combined radiation therapy with a drug (telaglenastat) that stops a key enzyme in a cell pathway that becomes altered in cancer cells, causing those cells to grow rapidly and resist treatment.
Wicker says this drug has already been studied in multiple clinical trials to see if it could improve treatment of various cancers.
“Until now, no one has examined if this drug has the potential to improve radiation treatment in head and neck cancer. Most importantly, this drug compound has been well tolerated by patients and causes minimal side effects,” she says.
Using animal models, researchers found that the drug alone reduced the growth of head and neck cancer cells up to 90%, and it also increased the efficacy of radiation in animals with head and neck tumors by 40%.
“With these results, and especially with previous clinical trials showing that the drug is well tolerated by patients, there is the potential to move more rapidly into head and neck cancer clinical trials,” Wicker says. “In the future, we hope this drug will be used to make radiation treatments for head and neck cancer even more effective.”
Currently, the most common treatment for that cancer is radiation therapy, but the cancer eventually returns in up to half of patients, Wicker says, and often it doesn’t respond as positively to treatment the second time around.
“When [traditional] drugs are less effective, cancer growth becomes difficult to control, which can lead to the cancer quickly spreading to other organs,” she says.
Cancer cells utilise glutamine to aid in the biosynthetic, bioenergetic and redox needs that are associated with proliferation [1,2,3,4]. Many Triple-receptor Negative Breast Cancer (TNBC) cell lines are particularly dependent on glutamine for growth and viability [5, 6]. These cells acquire glutamine and then convert it to glutamate in a reaction catalysed by mitochondrial glutaminase – predominantly the GAC splice variant encoded by the GLS gene [5, 6].
The glutamate derived from glutamine has many uses, including glutathione synthesis or further metabolism to α-ketoglutarate (αKG) by glutamate dehydrogenase/aminotransferase-catalysed reactions [1, 4]. This αKG contributes to numerous biosynthetic and epigenetic processes or can act as an anaplerotic substrate to replenish tricarboxylic acid (TCA) cycle metabolites that have been exported from the mitochondria for the production of biomass [3]. Once αKG enters the TCA cycle it can support TCA cycle flux either through oxidative decarboxylation or reductive carboxylation [7,8,9,10,11].
This dependence on glutamine anaplerosis renders TNBC cells at increased sensitivity to pharmacological glutaminase inhibition both in vitro and in vivo [6, 12, 13]. Clinically, glutaminase inhibition is emerging as a promising therapeutic avenue for the management of advanced TNBC. CB-839 (Telaglenastat) is a potent, selective, orally bioavailable first-in-class glutaminase inhibitor that has demonstrated promise in the management of metastatic TNBC in Phase I/II studies [14, 15].
When combined with paclitaxel, CB-839 was well tolerated with evidence of antitumour activity in heavily pre-treated patients. Yet, although an objective response rate (ORR) of 22% was observed in the Phase I study (doses ≥600 mg BID, n = 27), the outcome of the Phase II study was less encouraging with ORR of 6% (800 mg BID, n = 16, “Third Line +” cohort) [14, 15].
A greater mechanistic understanding of the pharmacology of glutaminase inhibition, development of rational drug combinations and the identification and validation of biomarkers may assist in further clinical development of glutaminase inhibitors for TNBC treatment.
While preclinical and clinical studies have confirmed the sensitivity of TNBC to glutaminase inhibition, additional reports in a variety of cancer types have uncovered a set of intrinsic and extrinsic determinants that can impair cellular sensitivity to glutaminase inhibitors.
Cells derived from mouse models of non-small cell lung cancer (NSCLC) were highly dependent on glutamine for TCA cycle anaplerosis and proliferation when grown in cell culture but utilised minimal glutamine when grown in vivo, relying instead on glucose metabolism to fuel the TCA cycle [16].
This finding along with results from clinical in vivo and ex vivo isotope tracer studies suggest that the tumour microenvironment has a strong influence on cellular metabolic programmes and the potential to influence the efficacy of metabolism-targeted therapies [17, 18].
One possible contributor for the loss of glutamine dependence observed in vivo is the lower cystine concentration in tumours compared with cell culture medium. Growing cells in vitro in physiological concentrations of cystine (20–50 μM) suppressed the level of glutamine anaplerosis and subsequently desensitised cells to CB-839 [19]. On the contrary, administering cystine to mice increased plasma cystine levels and promoted glutamine anaplerotic flux in subcutaneous tumour xenografts [19].
An additional, intrinsic cellular characteristic is required for this effect; the expression of the glutamate/cystine antiporter (xCT) subunit SLC7A11 promotes this cystine-dependent increase in glutamine utilisation resulting in glutamine dependence [19]. Many oncogenic processes promote the elevated expression of SLC7A11, including KEAP1 mutation and the subsequent NRF2 (NFE2L2)-driven antioxidant response [20].
A number of other metabolites have been identified that can reduce glutamine dependence. For example, increasing the levels of exogenous glutamate can support cell proliferation in times of glutamine deprivation or glutaminase inhibition [20,21,22,23]. Likewise, addition of pyruvate or oxaloacetate could prevent apoptosis during acute glutamine deprivation but was unable to support cell proliferation [24].
Addition of extracellular deoxynucleosides was also shown to render TNBC cells resistant to glutamine deprivation [25]. Yet, whether these extrinsic factors contribute to the decrease in glutamine metabolism observed in many tumours compared with in vitro conditions and the potential impact on antitumour activity of glutaminase inhibitors is unknown.
In this study we investigated a key difference in culture medium composition that can influence the sensitivity of TNBC cell lines to pharmacological glutaminase inhibition. We show that extracellular pyruvate, at physiological concentrations of 20–100 μM, can significantly impair CB-839 potency in vitro by acting as an anaplerotic substrate. Normal blood pyruvate concentration is reported in the range of 30–150 μM [26,27,28].
Furthermore, we demonstrate that paracrine secretion of de novo produced pyruvate into the extracellular environment can act as a source of pyruvate and this process can be antagonised using a monocarboxylate transporter 1 (MCT1) inhibitor. Our work highlights the potential for both systemic- and paracrine tumour-derived pyruvate to limit the antitumour activity of glutaminase inhibitors and uncovers a possible rational combination that includes addition of MCT1 inhibitor to glutaminase inhibitor therapy.
reference link:https://bmccancer.biomedcentral.com/articles/10.1186/s12885-020-06885-3
More information: Christina A. Wicker et al, Glutaminase inhibition with telaglenastat (CB-839) improves treatment response in combination with ionizing radiation in head and neck squamous cell carcinoma models, Cancer Letters (2021). DOI: 10.1016/j.canlet.2020.12.038
