Immunometabolic Adaptation of CD19-Targeted CAR T Cells in the Central Nervous System Microenvironment of Patients Promotes Memory Development.

Unlabelled: Metabolic reprogramming is a hallmark of T-cell activation, and metabolic fitness is fundamental for T-cell-mediated antitumor immunity. Insights into the metabolic plasticity of chimeric antigen receptor (CAR) T cells in patients could help identify approaches to improve their efficacy in treating cancer. Here, we investigated the spatiotemporal immunometabolic adaptation of CD19-targeted CAR T cells using clinical samples from CAR T-cell-treated patients.

Correction: 2'-Hydroxyflavanone effectively targets RLIP76-mediated drug transport and regulates critical signaling networks in breast cancer.

[This corrects the article DOI: 10.18632/oncotarget.24720.

Prevention of mammary carcinogenesis in MMTV-neu mice by targeting RLIP.

The overexpression and amplification of the protooncogene neu (ERBB2) play an important role in the development of aggressive breast cancer (BC) in humans. Ral-interacting protein (RLIP), a modular stress-response protein with pleiotropic functions, is overexpressed in several types of cancer, including BC. Here, we show that blocking RLIP attenuates the deleterious effects caused by the loss of the tumor suppressor p53 and inhibits the growth of human BC both in vitro and in vivo in MMTV-neu mice.

Activating p53 function by targeting RLIP.

Aberrations in RLIP, p53, and PKCα represent essentially the entire spectrum of all human neoplasms. Elevated PKCα expression, failure of the cell cycle checkpoint (p53 dysfunction), and abnormal glutathione (GSH) metabolism are fundamental hallmarks of carcinogenesis and drug/radiation resistance. However, a lack of investigations into the interactions between these important regulatory nodes has fundamentally limited our understanding of carcinogenesis and the development of effective interventions for cancer prevention and therapy.

Rlip Depletion Suppresses Growth of Breast Cancer.

RLIP76 (RAL-binding protein-1, Rlip) is a stress-protective mercapturic-acid-pathway transporter protein that also plays a key role in regulating clathrin-dependent endocytosis as a Ral effector. Targeted inhibition or depletion of Rlip causes regression of xenografts of many cancers and is capable of abrogating tumor formation in p53-null mice. This is associated with the reversion of the abnormal methylomic profile of p53-null mice to wild-type.

Targeting RLIP with CRISPR/Cas9 controls tumor growth.

Breast cancer (BC) remains one of the major causes of cancer deaths in women. Over half of all BCs carry genetic defects in the gene encoding p53, a powerful tumor suppressor. P53 is known as the 'guardian of the genome' because it is essential for regulating cell division and preventing tumor formation.

Therapeutic targeting of miRNA-216b in cancer.

MicroRNAs (miRNAs/or miR) are a type of small, non-coding RNAs that regulate gene expression by binding to 3'-UTRs of the target genes. miRNAs can serve as oncogenes or tumor suppressors, and have prognostic and therapeutic values that may be directly applicable in the clinic. miR-216b is located on chromosome 2p16.

SOX9: The master regulator of cell fate in breast cancer.

SRY-related high-mobility group box 9 (SOX9) is an indispensable transcription factor that regulates multiple developmental pathways related to stemness, differentiation, and progenitor development. Previous studies have demonstrated that the SOX9 protein directs pathways involved in tumor initiation, proliferation, migration, chemoresistance, and stem cell maintenance, thereby regulating tumorigenesis as an oncogene. SOX9 overexpression is a frequent event in breast cancer (BC) subtypes.

Elimination of human folypolyglutamate synthetase alters programming and plasticity of somatic cells.

Folates are vital cofactors for the regeneration of -adenosyl methionine, which is the methyl source for DNA methylation, protein methylation, and other aspects of one-carbon (C1) metabolism. Thus, folates are critical for establishing and preserving epigenetic programming. Folypolyglutamate synthetase (FPGS) is known to play a crucial role in the maintenance of intracellular folate levels.

Notch signaling in breast cancer: From pathway analysis to therapy.

The Notch signaling pathway, which is highly conserved from sea urchins to humans, plays an important role in cell-differentiation, survival, proliferation, stem-cell renewal, and determining cell fate during development and morphogenesis. It is well established that signaling pathways are dysregulated in a wide-range of diseases, including human malignancies. Studies suggest that the dysregulation of the Notch pathway contributes to carcinogenesis, cancer stem cell renewal, angiogenesis, and chemo-resistance.

Synergistic efficacy of RLIP inhibition and 2'-hydroxyflavanone against DMBA-induced mammary carcinogenesis in SENCAR mice.

Substantial evidence suggests that 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinogenesis in mice mimics human breast cancer (BC) in many respects. Therefore, it has been used extensively to evaluate preventive and therapeutic agents for human BC. Mammary carcinogenesis induced by DMBA administration in female SENsitive to CARcinogen (SENCAR) mice was characterized by histopathological analysis of the mammary glands and alterations to the phosphatidylinositol 3-kinase/protein kinase B/cyclin-dependent kinase 1 (PI3K/Akt/CDK1) pathway.

RLIP inhibition suppresses breast-to-lung metastasis.

Breast tumor metastasis is a leading cause of cancer-related deaths worldwide. Breast cancer (BC) cells frequently metastasize to the lungs, where they pose a formidable therapeutic challenge. In the current study, we evaluated the anti-proliferative and anti-metastatic effects of 2'-hydroxyflavanone (2HF) and RLIP inhibition in an array of triple-negative BC cell lines and an orthotopic mouse model of breast-to-lung metastasis.

Bioenergetic modulation with the mitochondria uncouplers SR4 and niclosamide prevents proliferation and growth of treatment-naïve and vemurafenib-resistant melanomas.

BRAF mutations are detected in >50% of all melanomas. These mutations impair the LKB1-AMPK signaling, an important metabolic pathway associated with cell growth, proliferation and survival. Melanoma patients with BRAF mutations are usually treated with BRAF inhibitors such as vemurafenib, but responses are short-lived as drug resistant tumors metabolically switch to mitochondrial oxidative phosphorylation (OXPHOS) to escape metabolic stress-induced BRAF inhibition.

Anticancer activity of 2'-hydroxyflavanone towards lung cancer.

In previous studies, we found that 2'-hydroxyflavonone (2HF), a citrus flavonoid, inhibits the growth of renal cell carcinoma in a VHL-dependent manner. This was associated with the inhibition of glutathione S-transferases (GSTs), the first step enzyme of the mercapturic acid pathway that catalyzes formation of glutathione-electrophile conjugates (GS-E). We studied 2HF in small cell (SCLC) and non-small cell (NSCLC) lung cancer cell lines for sensitivity to 2HF antineoplastic activity and to determine the role of the GS-E transporter Rlip (Ral-interacting protein; RLIP76; RALBP1) in the mechanism of action of 2HF.

2'-Hydroxyflavanone induced changes in the proteomic profile of breast cancer cells.

In spite of rapid advances in understanding of signaling networks associated with the incidence and therapeutic-sensitivity, breast cancer (BC) still remains the most commonly diagnosed and prevalent cancer in women. Emergence of resistance to hormonal interventions in estrogen-receptor (ER) positive BC coupled to loss of ER expression and activation of ER-independent growth factor, heat-shock, MYC and WNT pathways along with distinct mechanisms of therapeutic-resistance in HER2 over-expressing and triple-negative subtypes of BC collectively necessitates deeper profiling of the mechanistic networks regulated by potential lead anticancer compounds intended for further development to target BC. A significant part of the search for novel lead anticancer compounds for BC has focused on phytochemicals including flavonoids found in citrus fruits, which have shown promising anticancer activity.

Metastasis of breast tumor cells to brain is suppressed by targeting RLIP alone and in combination with 2'-Hydroxyflavanone.

Brain metastasis is an important cause of morbidity and mortality in cancer-patients. Breast tumor cells frequently metastasize to brain and initiate severe therapeutic complications. In the present study, we evaluated the anti-metastatic effects of 2'-hydroxyflavanone (2HF) alone and in combination with RLIP targeted therapy in a novel murine model of breast tumor metastasis.

2'-Hydroxyflavanone inhibits in vitro and in vivo growth of breast cancer cells by targeting RLIP76.

Consumption of citrus-fruits is associated with reduced incidence of breast cancer (BC), the most common cancer diagnosed in women across the globe. In this study, we investigated the anticancer potential of 2-Hydroxyflavanone (2HF) in BC. 2HF, a citrus-bioflavonoid, has demonstrated anticancer properties in various cancers, but its anticancer role in BC has not been well studied.

2'-Hydroxyflavanone effectively targets RLIP76-mediated drug transport and regulates critical signaling networks in breast cancer.

Breast cancer (BC) is the most common cancer in women. Estrogen, epidermal growth factor receptor 2 (ERBB2, HER2), and oxidative stress represent critical mechanistic nodes associated with BC. RLIP76 is a major mercapturic acid pathway transporter whose expression is increased in BC.

Rlip depletion prevents spontaneous neoplasia in TP53 null mice.

TP53 (p53) is a tumor suppressor whose functions are lost or altered in most malignancies. p53 homozygous knockout (p53) mice uniformly die of spontaneous malignancy, typically T-cell lymphoma. RALBP1 (RLIP76, Rlip) is a stress-protective, mercapturic acid pathway transporter protein that also functions as a Ral effector involved in clathrin-dependent endocytosis.

Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment.

Several epidemiological observations have shown an inverse relation between consumption of plant-based foods, rich in phytochemicals, and incidence of cancer. Phytochemicals, secondary plant metabolites, via their antioxidant property play a key role in cancer chemoprevention by suppressing oxidative stress-induced DNA damage. In addition, they modulate several oxidative stress-mediated signaling pathways through their anti-oxidant effects, and ultimately protect cells from undergoing molecular changes that trigger carcinogenesis.

2'-Hydroxyflavanone: A novel strategy for targeting breast cancer.

Breast cancer is the most common cancer in women that is driven by cross-talk with hormonal and cellular signaling pathways. The natural phytochemicals, due to broad-spectrum anti-inflammatory and anti-cancerous properties, present with novel opportunities for targeting breast cancer. Intake of citrus fruits is known to reduce the risk for incidence of breast cancer.

Translational opportunities for broad-spectrum natural phytochemicals and targeted agent combinations in breast cancer.

Breast cancer (BC) prevention and therapy in the context of life-style risk factors and biological drivers is a major focus of developmental therapeutics in oncology. Obesity, alcohol, chronic estrogen signaling and smoking have distinct BC precipitating and facilitating effects that may act alone or in combination. A spectrum of signaling events including enhanced oxidative stress and changes in estrogen-receptor (ER)-dependent and -independent signaling drive the progression of BC.

RLIP76 Inhibition: A Promising Developmental Therapy for Neuroblastoma.

Refractory and relapsed neuroblastoma (NB) present with significant challenges in clinical management. Though primary NBs largely with wild-type p53 respond well to interventions, dysfunctional signaling in the p53 pathways in a MYCN oncogene driven background is found in a number of children with NB. The p53-mutant NB is largely unresponsive to available therapies and p53-independent targeted therapeutics represents a vital need in pediatric oncology.

Targeting the mercapturic acid pathway and vicenin-2 for prevention of prostate cancer.

Prostate cancer (CaP) is often androgen-sensitive malignancy and regresses upon inhibition of androgen signaling. However, CaP, nearly always develops androgen resistance and progresses to aggressive and lethal androgen-independent CaP, which lacks satisfactory therapy. For metastatic CaP, patients are often treated with Taxotere (docetaxel), a cytoskeleton-targeted chemotherapy drug, that provides transient palliative benefit but to which patients rapidly develop drug-resistance.

Didymin: an orally active citrus flavonoid for targeting neuroblastoma.

Neuroblastoma, a rapidly growing yet treatment responsive cancer, is the third most common cancer of children and the most common solid tumor in infants. Unfortunately, neuroblastoma that has lost p53 function often has a highly treatment-resistant phenotype leading to tragic outcomes. In the context of neuroblastoma, the functions of p53 and MYCN (which is amplified in ~25% of neuroblastomas) are integrally linked because they are mutually transcriptionally regulated, and because they together regulate the catalytic activity of RNA polymerases.