Rethinking Oncologic Treatment Strategies with Interleukin-2.

High-dose recombinant human IL-2 (rhIL-2, aldesleukin) emerged as an important treatment option for selected patients with metastatic melanoma and metastatic renal cell carcinoma, producing durable and long-lasting antitumor responses in a small fraction of patients and heralding the potential of cancer immunotherapy. However, the adoption of high-dose rhIL-2 has been restricted by its severe treatment-related adverse event (TRAE) profile, which necessitates highly experienced clinical providers familiar with rhIL-2 administration and readily accessible critical care medicine support. Given the comparatively wide-ranging successes of immune checkpoint inhibitors and chimeric antigen receptor T cell therapies, there have been concerted efforts to significantly improve the efficacy and toxicities of IL-2-based immunotherapeutic approaches.

Secretory pathway Ca-ATPase SPCA2 regulates mitochondrial respiration and DNA damage response through store-independent calcium entry.

A complex interplay between the extracellular space, cytoplasm and individual organelles modulates Ca signaling to impact all aspects of cell fate and function. In recent years, the molecular machinery linking endoplasmic reticulum stores to plasma membrane Ca entry has been defined. However, the mechanism and pathophysiological relevance of store-independent modes of Ca entry remain poorly understood.

ALT neuroblastoma chemoresistance due to telomere dysfunction-induced ATM activation is reversible with ATM inhibitor AZD0156.

Cancers overcome replicative immortality by activating either telomerase or an alternative lengthening of telomeres (ALT) mechanism. ALT occurs in ~25% of high-risk neuroblastomas, and progression in patients with ALT neuroblastoma during or after front-line therapy is frequent and often fatal. Temozolomide + irinotecan is commonly used as salvage therapy for neuroblastoma.

Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells.

The secretory pathway Ca-ATPase SPCA2 is a tumor suppressor in triple receptor negative breast cancer (TNBC), a highly aggressive molecular subtype that lacks tailored treatment options. Low expression of SPCA2 in TNBC confers poor survival prognosis in patients. Previous work has established that re-introducing SPCA2 to TNBC cells restores basal Ca signaling, represses mesenchymal gene expression, mitigates tumor migration in vitro and metastasis in vivo.

The O6-methyguanine-DNA methyltransferase inhibitor O6-benzylguanine enhanced activity of temozolomide + irinotecan against models of high-risk neuroblastoma.

DNA-damaging chemotherapy is a major component of therapy for high-risk neuroblastoma, and patients often relapse with treatment-refractory disease. We hypothesized that DNA repair genes with increased expression in alkylating agent resistant models would provide therapeutic targets for enhancing chemotherapy. In-vitro cytotoxicity of alkylating agents for 12 patient-derived neuroblastoma cell lines was assayed using DIMSCAN, and mRNA expression of 57 DNA repair, three transporter, and two glutathione synthesis genes was assessed by TaqMan low-density array (TLDA) with further validation by qRT-PCR in 26 cell lines.

Vorinostat and fenretinide synergize in preclinical models of T-cell lymphoid malignancies.

T-cell lymphoid malignancies (TCLMs) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitors and the synthetic cytotoxic retinoid fenretinide have achieved durable clinical responses in T-cell lymphomas as single agents, and patients who failed prior HDAC inhibitor treatment have responded to fenretinide. We have previously shown fenretinide synergized with the class I HDAC inhibitor romidepsin in preclinical models of TCLMs.

MYC transcription activation mediated by OCT4 as a mechanism of resistance to 13-cisRA-mediated differentiation in neuroblastoma.

Despite the improvement in clinical outcome with 13-cis-retinoic acid (13-cisRA) + anti-GD2 antibody + cytokine immunotherapy given in first response ~40% of high-risk neuroblastoma patients die of recurrent disease. MYCN genomic amplification is a biomarker of aggressive tumors in the childhood cancer neuroblastoma. MYCN expression is downregulated by 13-cisRA, a differentiating agent that is a component of neuroblastoma therapy.

Sarcoma as Second Cancer in a Childhood Cancer Survivor: Case Report, Large Population Analysis and Literature Review.

The majority of pediatric patients are cured of their primary cancer with current advanced developments in pediatric cancer therapy. However, survivors often experience long-term complications from therapies for primary cancer. The delayed mortality rate has been decreasing with the effort to reduce the therapeutic exposure of patients with pediatric cancers.

Large Population Analysis of Secondary Cancers in Pediatric Leukemia Survivors.

Introduction: Survivors of childhood cancer have an increased risk of developing a subsequent secondary malignant neoplasm (SMN). Among five-year survivors of primary cancer, SMNs account for nearly half of non-relapse deaths, which make them the most frequent cause of non-relapse mortality. Leukemia is the most common childhood cancer and the five-year survival rate of leukemia has drastically improved over the past two decades.

Subtype specific targeting of calcium signaling in breast cancer.

An important component of breast milk, calcium also appears as radiographically prominent microcalcifications in breast tissue that are often the earliest sign of malignancy. Ionic Ca is a universal second messenger that controls a wide swathe of effector pathways integral to gene transcription, cell cycle control, differentiation, proliferation, cell migration, and apoptosis. Whereas prolonged elevation in resting Ca levels drives proliferation to initiate and sustain tumor growth, depletion of calcium stores and attenuation of calcium influx pathways underlies tumor chemoresistance and evasion of apoptosis.

Fenretinide via NOXA Induction, Enhanced Activity of the BCL-2 Inhibitor Venetoclax in High BCL-2-Expressing Neuroblastoma Preclinical Models.

Recurrent high-risk neuroblastoma is a childhood cancer that often fails to respond to therapy. Fenretinide (4-HPR) is a cytotoxic retinoid with clinical activity in recurrent neuroblastoma and venetoclax (ABT-199) is a selective inhibitor of the antiapoptotic protein B-cell lymphoma-2 (BCL-2). We evaluated activity of 4-HPR + ABT-199 in preclinical models of neuroblastoma.

Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance.

Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies.

A Ca-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells.

Progression of benign tumors to invasive, metastatic cancer is accompanied by the epithelial-to-mesenchymal transition (EMT), characterized by loss of the cell-adhesion protein E-cadherin. Although silencing mutations and transcriptional repression of the E-cadherin gene have been widely studied, not much is known about posttranslational regulation of E-cadherin in tumors. We show that E-cadherin is tightly coexpressed with the secretory pathway Ca-ATPase isoform 2, SPCA2 (), in breast tumors.

Regulation of Chemokines and Cytokines by Histone Deacetylases and an Update on Histone Decetylase Inhibitors in Human Diseases.

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) counteract with each other to regulate gene expression by altering chromatin structure. Aberrant HDAC activity was reported in many human diseases including wide range of cancers, viral infections, cardiovascular complications, auto-immune diseases and kidney diseases. HDAC inhibitors are small molecules designed to block the malignant activity of HDACs.

Advancement of NF-κB Signaling Pathway: A Novel Target in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers and is the third highest among cancer related deaths. Despite modest success with therapy such as gemcitabine, pancreatic cancer incidence remains virtually unchanged in the past 25 years. Among the several driver mutations for PDAC, mutation contributes a central role for its development, progression and therapeutic resistance.

Cancer stem cells: Road to therapeutic resistance and strategies to overcome resistance.

Unlike other normal cells, a subpopulation of cells often termed as "stem cells" are long-lived and generate cellular progeny throughout life. Cancer stem cells (CSCs) are rare immortal cells within a tumor that can both self-renew by dividing and giving rise to many cell types that constitute the tumor. CSCs also have been shown to be involved in fundamental processes of cell proliferation and metastatic dissemination.