Publications by authors named "Wafik S El-Deiry"

333 Publications

Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in refractory adult T-Cell leukemia/lymphoma.

Cancer Biol Ther 2022 12;23(1):417-423

Division of Hematology/Oncology, Brown University and the Lifespan Cancer Institute, Providence, RI, USA.

GSK-3β is a serine/threonine kinase implicated in tumorigenesis and chemotherapy resistance. GSK-3β blockade downregulates the NF-κB pathway, modulates immune cell PD-1 and tumor cell PD-L1 expression, and increases CD8 + T cell and NK cell function. We report a case of adult T-cell leukemia/lymphoma (ATLL) treated with 9-ING-41, a selective GSK-3β inhibitor in clinical development, who achieved a durable response. A 43-year-old male developed diffuse lymphadenopathy, and biopsy of axillary lymph node showed acute-type ATLL. Peripheral blood flow cytometry revealed a circulating clonal T cell population, and CSF was positive for ATLL involvement. After disease progression on the 3 line of treatment, he started treatment with 9-ING-41 monotherapy in a clinical trial (NCT03678883). CT imaging after seven months showed a partial response. Sustained reduction of peripheral blood ATLL cells lasted 15 months. Treatment of patient-derived CD8 + T cells with 9-ING-41 increased the secretion of IFN-γ, granzyme B, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In conclusion, treatment of a patient with refractory ATLL with the GSK-3β inhibitor 9-ING-41 resulted in a prolonged response. Ongoing experiments are investigating the hypothesis that 9-ING-41-induced T cell activation and immunomodulation contributes to its clinical activity. Further clinical investigation of 9-ING-41 for treatment of ATLL is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15384047.2022.2088984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272832PMC
December 2022

amplification and deletion in metastatic melanoma and glioblastoma multiforme may have implications for targeted therapeutics and immunotherapy.

Am J Cancer Res 2022 15;12(5):2102-2117. Epub 2022 May 15.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University Providence, RI, USA.

Metastatic melanoma has a five-year survival of ~10%, with a paucity of biomarkers predicting metastasis to specific anatomic sites or targeted therapies for metastases. We analyzed 1015 primary and 358 metastatic melanomas and found metastatic disease is enriched for and amplifications compared to primary disease, and amplifications are associated with lower overall survival. amplifications are associated with a higher rate of metastasis to the brain and liver. Two negative regulators of p53, and , are also altered in metastatic melanoma compared to primary disease. These findings suggest that patients with metastatic melanoma have a dysregulated TP53 pathway compared to primary disease. We propose that patients with metastatic melanoma and wild-type may be more likely to benefit from MDM2, MDM4, USP7, and PPM1D inhibitors. Patients with amplification display deep deletions in , alterations also associated with a higher rate of metastasis to the brain. Patients with a deletion have a higher rate of alterations in , and , alterations previously associated with favorable response to immune-checkpoint inhibitors in melanoma. We propose alteration as a potential biomarker to predict response to immunotherapy in melanoma. We found that GBM displays the highest rate of amplifications (9.63%) and deletions (54.39%) across all cancer types. In 592 GBM samples we found that 8.45% display amplification. We suggest that patients with melanoma or GBM and amplifications in and alterations may benefit from combinations of targeted inhibitors of MDM2/4 and CDK4/6, as well as immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9185629PMC
May 2022

Oral administration of TRAIL-inducing small molecule ONC201/TIC10 prevents intestinal polyposis in the mouse model.

Am J Cancer Res 2022 15;12(5):2118-2131. Epub 2022 May 15.

Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center Oklahoma City, OK, USA.

Colorectal cancer (CRC) incidence is rising globally. Hence, preventing this disease is a high priority. With this aim, we determined the CRC prevention potential of the TRAIL-inducing small molecule ONC201/TIC10 using a preclinical model representing high-risk familial adenomatous polyposis (FAP) patients, mice. Prior to the efficacy study, optimal and non-toxic doses of ONC201 were determined by testing five different doses of ONC201 (0-100 mg/kg body weight (BW); twice weekly by oral gavage) in C57BL/6J mice (=6/group) for 6 weeks. BW gain, organ weights and histopathology, blood profiling, and the plasma liver enzyme profile suggested no toxicities of ONC201 at doses up to 100 mg/kg BW. For efficacy determination, beginning at six weeks of age, groups of male and female mice (≥20) treated with colon carcinogen azoxymethane (AOM) (AOM- ) were administered ONC201 (0, 25, and 50 mg/kg BW) as above up to 20 weeks of age. At termination, efficacy was determined by comparing the incidence and multiplicity of intestinal tumors between vehicle- and drug-treated groups. ONC201 showed a strong suppressive effect against the development of both large and small intestinal tumors in male and female mice. mice treated with ONC201 (50 mg/kg BW) showed >50% less colonic tumor incidence (<0.0002) than controls. Colonic tumor multiplicity was also significantly reduced by 68% in male mice (0.44 ± 0.11 in treated vs. 1.4 ± 0.14 in controls; <0.0001) and by 75% in female mice (0.30 ± 0.10 in treated vs. 1.19 ± 0.19 in controls; <0.0003) with ONC201 treatment (50 mg/kg BW). Small intestinal polyps were reduced by 68% in male mice (11.40 ± 1.19 in treated vs. 36.08 ± 2.62 in controls; <0.0001) and female mice (9.65 ± 1.15 in treated vs. 29.24 ± 2.51 in controls; <0.0001). Molecular analysis of the tumors suggested an increase in TRAIL, DR5, cleaved caspases 3/7/8, Fas-associated death domain protein (FADD), and p21 (WAF1) in response to drug treatment. Serum analysis indicated a decrease in pro-inflammatory serum biomarkers, such as IL1β, IL6, TNFα, G-CSF, and GM-CSF, in the ONC201-treated mice compared with controls. Our data demonstrated excellent chemopreventive potential of orally administered ONC201 against intestinal tumorigenesis in the AOM- mouse model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9185612PMC
May 2022

Integrin/TGF-β1 Inhibitor GLPG-0187 Blocks SARS-CoV-2 Delta and Omicron Pseudovirus Infection of Airway Epithelial Cells In Vitro, Which Could Attenuate Disease Severity.

Pharmaceuticals (Basel) 2022 May 17;15(5). Epub 2022 May 17.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.

As COVID-19 continues to pose major risk for vulnerable populations, including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins, either independently or as a co-receptor with surface receptor angiotensin-converting enzyme 2 (ACE2). We used pan-integrin inhibitor GLPG-0187 to demonstrate the blockade of SARS-CoV-2 pseudovirus infection of target cells. Omicron pseudovirus infected normal human small airway epithelial (HSAE) cells significantly less than D614G or Delta variant pseudovirus, and GLPG-0187 effectively blocked SARS-CoV-2 pseudovirus infection in a dose-dependent manner across multiple viral variants. GLPG-0187 inhibited Omicron and Delta pseudovirus infection of HSAE cells more significantly than other variants. Pre-treatment of HSAE cells with MEK inhibitor (MEKi) VS-6766 enhanced the inhibition of pseudovirus infection by GLPG-0187. Because integrins activate transforming growth factor beta (TGF-β) signaling, we compared the plasma levels of active and total TGF-β in COVID-19+ patients. The plasma TGF-β1 levels correlated with age, race, and number of medications upon presentation with COVID-19, but not with sex. Total plasma TGF-β1 levels correlated with activated TGF-β1 levels. Moreover, the inhibition of integrin signaling prevents SARS-CoV-2 Delta and Omicron pseudovirus infectivity, and it may mitigate COVID-19 severity through decreased TGF-β1 activation. This therapeutic strategy may be further explored through clinical testing in vulnerable and unvaccinated populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ph15050618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9143518PMC
May 2022

Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer.

Biomolecules 2022 04 6;12(4). Epub 2022 Apr 6.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.

is a tumor suppressor gene that encodes a sequence-specific DNA-binding transcription factor activated by stressful stimuli; it upregulates target genes involved in growth suppression, cell death, DNA repair, metabolism, among others. is the most frequently mutated gene in tumors, with mutations not only leading to loss-of-function (LOF), but also gain-of-function (GOF) that promotes tumor progression, and metastasis. The tumor-specific status of mutant p53 protein has suggested it is a promising target for cancer therapy. We summarize the current progress of targeting wild-type and mutant p53 for cancer therapy through biotherapeutic and biopharmaceutical methods for (1) boosting p53 activity in cancer, (2) p53-dependent and p53-independent strategies for targeting p53 pathway functional restoration in p53-mutated cancer, (3) targeting p53 in immunotherapy, and (4) combination therapies targeting p53, p53 checkpoints, or mutant p53 for cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom12040548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029346PMC
April 2022

Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma.

Clin Cancer Res 2022 06;28(12):2704-2714

Caris Life Sciences, Phoenix, Arizona.

Purpose: KRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). A small subset of PDACs harbor KRAS wild-type (WT). We aim to characterize the molecular profiles of KRAS WT PDAC to uncover new pathogenic drivers and offer targeted treatments.

Experimental Design: Tumor tissue obtained from surgical or biopsy material was subjected to next-generation DNA/RNA sequencing, microsatellite instability (MSI) and mismatch repair status determination.

Results: Of the 2,483 patients (male 53.7%, median age 66 years) studied, 266 tumors (10.7%) were KRAS WT. The most frequently mutated gene in KRAS WT PDAC was TP53 (44.5%), followed by BRAF (13.0%). Multiple mutations within the DNA-damage repair (BRCA2, ATM, BAP1, RAD50, FANCE, PALB2), chromatin remodeling (ARID1A, PBRM1, ARID2, KMT2D, KMT2C, SMARCA4, SETD2), and cell-cycle control pathways (CDKN2A, CCND1, CCNE1) were detected frequently. There was no statistically significant difference in PD-L1 expression between KRAS WT (15.8%) and MT (17%) tumors. However, KRAS WT PDAC were more likely to be MSI-high (4.7% vs. 0.7%; P < 0.05), tumor mutational burden-high (4.5% vs. 1%; P < 0.05), and exhibit increased infiltration of CD8+ T cells, natural killer cells, and myeloid dendritic cells. KRAS WT PDACs exhibited gene fusions of BRAF (6.6%), FGFR2 (5.2%), ALK (2.6%), RET (1.3%), and NRG1 (1.3%), as well as amplification of FGF3 (3%), ERBB2 (2.2%), FGFR3 (1.8%), NTRK (1.8%), and MET (1.3%). Real-world evidence reveals a survival advantage of KRAS WT patients in overall cohorts as well as in patients treated with gemcitabine/nab-paclitaxel or 5-FU/oxaliplatin.

Conclusions: KRAS WT PDAC represents 10.7% of PDAC and is enriched with targetable alterations, including immuno-oncologic markers. Identification of KRAS WT patients in clinical practice may expand therapeutic options in a clinically meaningful manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-3581DOI Listing
June 2022

Preclinical studies with ONC201/TIC10 and lurbinectedin as a novel combination therapy in small cell lung cancer (SCLC).

Am J Cancer Res 2022 15;12(2):729-743. Epub 2022 Feb 15.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University Providence, Rhode Island 02903, USA.

The American Cancer Society estimates that ~15% of all lung cancers are categorized as small cell lung cancer (SCLC) with an overall five-year survival rate of less than 7%. Due to disease aggressiveness, more other malignancies, the standard of care is based on clinical efficacy rather than helpful biomarkers. Lurbinectedin is a small molecule RNA polymerase II inhibitor that binds the minor groove of DNA to induce double-strand breaks. Lurbinectedin has efficacy towards SCLC cells at sub-nM concentration and received accelerated FDA approval in 2020 for metastatic SCLC that progressed on platinum-based therapy. ONC201/TIC10 is a TRAIL pathway-inducing compound that with demonstrated clinical efficacy in H3K27M-mutated diffuse midline glioma and neuroendocrine tumors, in early phase clinical trials. We hypothesized that combining ONC201 and lurbinectedin may yield synergistic and targeted killing of SCLC cells. SCLC cell lines H1048, H1105, H1882, and H1417 were treated with ONC201 and lurbinectedin and cell viability was determined using a CellTiter-Glo assay using varying drug concentrations. Synergistic growth inhibition of SCLC cells was noted with combination of ONC201 and lurbinectedin. Induction of the integrated stress response mediator ATF4 and CHOP was observed with ONC201 and lurbinectedin along with induction of PARP cleavage indicative of apoptosis in response to cellular stress. Additionally, SCLC lines treated with the combination therapy displayed increased DNA breakage-related proteins such as phosphorylated Chk-1, Wee1 and γ-H2AX. Combination index revealed the most potent synergy occurred at the concentrations of 0.16 μM ONC201 and 0.05 nM lurbinectedin in the H1048 cell line, demonstrating highly efficient and selective killing of these tumor cells . While these therapies showed potency against the cell lines derived from SCLC patients, it is noteworthy that the combination showed significantly less toxicity to healthy human lung epithelial cells. Future studies could explore the combination of ONC201 and lurbinectedin in SCLC cell lines, SCLC patient-derived organoids, other tumor types, including in vivo studies and clinical translation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8900004PMC
February 2022

Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers.

Cancers (Basel) 2022 Feb 17;14(4). Epub 2022 Feb 17.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.

Though early-stage colorectal cancer has a high 5 year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair-proficient patients to immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers14041028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8869923PMC
February 2022

miR-3132 upregulates surface TRAIL to induce apoptotic cell death in cancer cells.

Am J Cancer Res 2022 15;12(1):315-326. Epub 2022 Jan 15.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center Philadelphia, PA, USA.

TRAIL-based therapies are of significant clinical interest because of its unique ability to induce apoptosis in cancer cells while sparing normal and untransformed cells. This selective antitumor potential of the TRAIL pathway has been harnessed by development of therapeutics including recombinant (rh)TRAIL and TRAIL-receptor agonist antibodies such as mapatumumab and lexatumumab. While these TRAIL-based therapies have proven successful in preclinical studies and safe in early phase clinical trials, the limited serum half-life has been a hurdle for further clinical development. Here we characterize miR-3132, a novel and first-in class TRAIL-inducing miRNA with potent anti-proliferative and pro-apoptotic effects in cancer cell lines. Initial mechanistic studies indicate that miR-3132 engages the interferon signaling pathway to induce TRAIL and subsequent TRAIL-dependent apoptosis in cancer cell lines. Our data further suggests that the binding of miR-3132 to toll-like receptors could be the upstream pathway for the interferon response. The current study the first report to demonstrate miR-3132's efficacy and preliminary mechanism of action in cancer cell lines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8822281PMC
January 2022

Colorectal cancer extracellular acidosis decreases immune cell killing and is partially ameliorated by pH-modulating agents that modify tumor cell cytokine profiles.

Am J Cancer Res 2022 15;12(1):138-151. Epub 2022 Jan 15.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University Providence, RI 02912, USA.

Tumor cells upregulate myriad proteins that are important for pH regulation, resulting in the acidification of the extracellular tumor microenvironment (TME). Abnormal pH is known to dampen immune function, resulting in a worsened anti-tumor immune response. Understanding how extrinsic alterations in pH modulate the interactions between immune cells and tumors cells will help elucidate opportunities for new therapeutic approaches. We observed that pH impacts the function of immune cells, both natural killer (NK) and T cells, which is relevant in the context of a highly acidic TME. Decreased NK and T cell activity was correlated with decreasing pH in a co-culture immune cell-mediated tumor cell-killing assay. The addition of pH-modulating drugs cariporide, lansoprazole, and acetazolamide to the co-culture assay was able to partially mitigate this dampened immune cell function. Treatment of colorectal cancer (CRC) cells with NHE1 inhibitor cariporide increased CRC cell-secreted cytokines involved in immune cell recruitment and activation and decreased cytokines involved in epithelial-mesenchymal transition (EMT). Cariporide treatment also decreased CRC cell shed TRAIL-R2, TRAIL-R3, and PD-L1 which is relevant in the context of immunotherapy. These experiments can help inform future investigations into how the pH of the tumor microenvironment may be extrinsically modulated to improve anti-tumor immune response in solid tumors such as colorectal cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8822272PMC
January 2022

Integrin/TGF-β1 inhibitor GLPG-0187 blocks SARS-CoV-2 Delta and Omicron pseudovirus infection of airway epithelial cells which could attenuate disease severity.

medRxiv 2022 Jan 3. Epub 2022 Jan 3.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

As COVID-19 continues to pose major risk for vulnerable populations including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins either independently or as a co-receptor with surface receptor angiotensin-converting enzyme 2 (ACE2). We used pan-integrin inhibitor GLPG-0187 to demonstrate blockade of SARS-CoV-2 pseudovirus infection of target cells. Omicron pseudovirus infected normal human small airway epithelial (HSAE) cells significantly less than D614G or Delta variant pseudovirus, and GLPG-0187 effectively blocked SARS-CoV-2 pseudovirus infection in a dose-dependent manner across multiple viral variants. GLPG-0187 inhibited Omicron and Delta pseudovirus infection of HSAE cells more significantly than other variants. Pre-treatment of HSAE cells with MEK inhibitor (MEKi) VS-6766 enhanced inhibition of pseudovirus infection by GLPG-0187. Because integrins activate TGF-β signaling, we compared plasma levels of active and total TGF-β in COVID-19+ patients. Plasma TGF-β1 levels correlated with age, race, and number of medications upon presentation with COVID-19, but not with sex. Total plasma TGF-β1 levels correlated with activated TGF-β1 levels. In our preclinical studies, Omicron infects lower airway lung cells less efficiently than other COVID-19 variants. Moreover, inhibition of integrin signaling prevents SARS-CoV-2 Delta and Omicron pseudovirus infectivity, and may mitigate COVID-19 severity through decreased TGF-β1 activation. This therapeutic strategy may be further explored through clinical testing in vulnerable and unvaccinated populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2022.01.02.22268641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750711PMC
January 2022

Chemotherapy-induced cytokines and prognostic gene signatures vary across breast and colorectal cancer.

Am J Cancer Res 2021 15;11(12):6086-6106. Epub 2021 Dec 15.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University Providence, RI 02903, USA.

The mechanisms by which chemotherapeutic drugs mediate efficacy and toxicity in patients across cancers are not fully understood. A poorly understood aspect of the tumor cell response to chemotherapy is cytokine regulation. Some drug-induced cytokines promote the anti-cancer activity of the drugs, but others may promote proliferation, metastasis, and drug resistance. We evaluated effects of clinical chemotherapeutics oxaliplatin, cisplatin, 5-fluorouracil (5-FU), doxorubicin, paclitaxel, docetaxel, and carboplatin on a panel of 52 cytokines in MCF7 breast cancer (BC) cells. We observed pan-drug effects, such as the upregulation of TRAIL-R2 and Chitinase 3-like 1 and drug-specific effects on interleukin and CXCL cytokines. We compared cytokine regulation in MCF7 BC and HCT116 colorectal cancer (CRC) cells, revealing tissue-specific drug effects such as enhanced upregulation of TRAIL-R2 and downregulation of IFN-β and TRAIL in MCF7 by cisplatin, oxaliplatin, and 5-FU. We found that chemotherapy-inducible transcripts have varying potential for prognostic significance in CRC versus BC. Among the non-prognostic CRC genes that were prognostic in BC were NFKBIA and GADD45A, both of which support anti-cancer drug mechanisms. Thus, we establish a novel 7-drug, 52-cytokine signature in MCF7 BC cells and a 3-drug, 40-cytokine signature in HCT116 CRC cells that suggest drug-specific and tissue-specific cytokine regulation. Distinct differences across prognostic gene signatures in BC and CRC further support tissue specificity in the relative impact of drug-regulated genes on patient survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8727797PMC
December 2021

Small-Molecule NSC59984 Induces Mutant p53 Degradation through a ROS-ERK2-MDM2 Axis in Cancer Cells.

Mol Cancer Res 2022 04;20(4):622-636

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, Rhode Island.

Increased reactive oxygen species (ROS) and hyperstabilized mutant p53 are common in cancer. Hyperstabilized mutant p53 contributes to its gain of function (GOF) which confers resistance to chemotherapy and radiotherapy. Targeting mutant p53 degradation is a promising cancer therapeutic strategy. We used a small-molecule NSC59984 to explore elimination of mutant p53 in cancer cells, and identified an inducible ROS-ERK2-MDM2 axis as a vulnerability for induction of mutant p53 degradation in cancer cells. NSC59984 treatment promotes a constitutive phosphorylation of ERK2 via ROS in cancer cells. The NSC59984-sustained ERK2 activation is required for MDM2 phosphorylation at serine-166. NSC59984 enhances phosphorylated-MDM2 binding to mutant p53, which leads to mutant p53 ubiquitination and degradation. High cellular ROS increases the efficacy of NSC59984 targeting mutant p53 degradation and antitumor effects. Our data suggest that mutant p53 stabilization has a vulnerability under high ROS cellular conditions, which can be exploited by compounds to target mutant p53 protein degradation through the activation of a ROS-ERK2-MDM2 axis in cancer cells.

Implications: An inducible ROS-ERK2-MDM2 axis exposes a vulnerability in mutant p53 stabilization and can be exploited by small-molecule compounds to induce mutant p53 degradation for cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-21-0149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8983457PMC
April 2022

Therapeutic Targeting of Autophagy in Pancreatic Ductal Adenocarcinoma.

Front Pharmacol 2021 30;12:751568. Epub 2021 Nov 30.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by early metastasis, late detection, and poor prognosis. Progress towards effective therapy has been slow despite significant efforts. Novel treatment approaches are desperately needed and autophagy, an evolutionary conserved process through which proteins and organelles are recycled for use as alternative energy sources, may represent one such target. Although incompletely understood, there is growing evidence suggesting that autophagy may play a role in PDAC carcinogenesis, metastasis, and survival. Early clinical trials involving autophagy inhibiting agents, either alone or in combination with chemotherapy, have been disappointing. Recently, evidence has demonstrated synergy between the MAPK pathway and autophagy inhibitors in PDAC, suggesting a promising therapeutic intervention. In addition, novel agents, such as ONC212, have preclinical activity in pancreatic cancer, in part through autophagy inhibition. We discuss autophagy in PDAC tumorigenesis, metabolism, modulation of the immune response, and preclinical and clinical data with selected autophagy modulators as therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.751568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8670090PMC
November 2021

CDKN1A/p21, RB1, ARID1A, FLG, and HRNR mutation patterns provide insights into urinary tract environmental exposure carcinogenesis and potential treatment strategies.

Am J Cancer Res 2021 15;11(11):5452-5471. Epub 2021 Nov 15.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University Providence, RI, USA.

Bladder carcinoma has a 6% 5-year survival-rate for metastatic disease, with poorly understood links between genetic and environmental drivers of disease development, progression, and treatment response. Rhode Island has among the highest annual age-adjusted incidence rate of bladder cancer at 26.0/100,000, compared to 20.0 in the US, with a paucity of known driver genes for targeted therapies or predictive biomarkers. Bladder carcinomas have the highest frequency of alterations in CDKN1A/p21 (10%) across all cancer types analyzed in The Cancer Genome Atlas (TCGA) PanCancer Atlas Studies, displaying a predominance of truncating mutations (86%). We found that lung carcinomas lack CDKN1A truncating mutations, despite the shared role of tobacco as a risk factor for bladder cancer. Bladder carcinomas also have the highest frequency of RB1 alterations in TCGA (25%). We find that chromophobe renal cell carcinomas with CDKN1A and RB1 mutations are 100% truncating. Analysis of 1,868 bladder tumors demonstrated that truncating CDKN1A mutations co-occur with truncating RB1 mutations, suggesting an environmental exposure signature. Moreover, we found that HRNR and FLG mutations are enriched in tumors with CDKN1A alteration, suggesting potential novel roles in promoting bladder tumorigenesis. Association of HRNR with AKT activation offers possible therapeutic avenues, and FLG may provide insight into carcinogen exposure within the bladder. We suggest that because APOBEC mutations largely shape the bladder cancer mutational landscape, these events likely contribute to dysfunctional DNA repair genes, leading to frameshifts and the predominance of truncations in CDKN1A, RB1, ARID1A, or other drivers. We propose that patients with co-occurrence of CDKN1A and RB1 truncations may display enhanced responsiveness to targeted therapies combining cisplatin with ATR, ATM, CHK1, and CHK2 inhibitors, expanding therapeutic options for patients in need of improved precision treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640812PMC
November 2021

Combination of ONC201 and TLY012 induces selective, synergistic apoptosis in vitro and significantly delays PDAC xenograft growth in vivo.

Cancer Biol Ther 2021 12 2;22(10-12):607-618. Epub 2021 Dec 2.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, United States (US).

The five-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained a dismal 9% for approximately 40 years with an urgent need for novel therapeutic interventions. ONC201 is the founding member of the imipridone class, comprised of orally bioavailable small molecules that have shown efficacy in multiple tumor types both in animal models and in Phase I/II clinical trials. ONC201 is a potent inducer of the tumor necrosis factor related apoptosis inducing ligand (TRAIL) pathway. TRAIL is an innate immune mechanism which induces programmed cell death of cancer cells. We observed that PDAC cells upregulated ATF4, CHOP, and DR5 after treatment with ONC201. This occurred in cell lines that are susceptible to ONC201-induced apoptosis and in ones that are not. In response to ONC201, PDAC cells downregulated anti-apoptotic proteins including c-FLIP, BclXL, XIAP, cIAP1, and survivin. We hypothesized that TRAIL receptor agonists might induce selective, synergistic apoptosis in pancreatic cancer cell lines treated with ONC201. We screened 7 pancreatic cancer cell lines and found synergy with ONC201 and rhTRAIL or the novel TRAIL receptor agonist TLY012 in 6 of the 7 cell lines tested. experiments using BxPC3 and HPAFII xenograft models showed that the combination of ONC201 plus TLY012 significantly delays tumor growth as compared to controls. Immunohistochemical analysis of the tumors after three doses of the combination showed significantly increased cleavage of caspase 3 as compared to controls. Taken together, the preclinical efficacy of ONC201 and TLY012 represents a novel therapeutic option for further testing in pancreatic cancer patients. This combination showed marked efficacy in tumor cells that are both sensitive and resistant to the pro-apoptotic effects of ONC201, providing rationale to further investigate the combination of ONC201 plus TLY012 in patients with pancreatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15384047.2021.1976567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726623PMC
December 2021

Molecular characterization of squamous cell carcinoma of the anal canal.

J Gastrointest Oncol 2021 Oct;12(5):2423-2437

Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.

Background: Squamous cell carcinoma of the anal canal (SCCA) is an uncommon malignancy with limited therapeutic options. Nivolumab and pembrolizumab show promising results in patients with SCCA. Human papillomavirus (HPV)-negative tumors are frequently -mutated (MT) and often resistant to therapy.

Methods: We present a large molecularly-profiled cohort of SCCA, exploring the underlying biology of SCCA, differences between -wild type (WT) and -MT tumors, and differences between local and metastatic tumors. SCCA specimens (n=311) underwent multiplatform testing with immunohistochemistry (IHC), in situ hybridization (ISH) and next-generation sequencing (NGS). Tumor mutational burden (TMB) was calculated using only somatic nonsynonymous missense mutations. Chi-square testing was used for comparative analyses.

Results: The most frequently mutated genes included (28.1%), (19.5%), (12%), (12%) and (10.8%). The expression of PD-1 was seen in 68.8% and PD-L1 in 40.5% of tumors. High TMB was present in 6.7% of specimens. HER2 IHC was positive in 0.9%, amplification by chromogenic in situ hybridization (CISH) was seen 1.3%, and mutations in were present in 1.8% of tumors. The latter mutation has not been previously described in SCCA. When compared with TP53-WT tumors, TP53-MT tumors had higher rates of , and mutations. PD-1 and PD-L1 expression were similar, and high TMB did not correlate with PD-1 (P=0.50) or PD-L1 (P=0.52) expression.

Conclusions: Molecular profiling differences between -MT and TP53-WT SCCA indicate different carcinogenic pathways which may influence response to therapy. Low frequency mutations in several druggable genes may provide therapeutic opportunities for patients with SCCA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jgo-20-610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576238PMC
October 2021

Differential p53-Mediated Cellular Responses to DNA-Damaging Therapeutic Agents.

Int J Mol Sci 2021 Oct 31;22(21). Epub 2021 Oct 31.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.

The gene , which encodes the tumor suppressor protein p53, is mutated in about 50% of cancers. In response to cell stressors like DNA damage and after treatment with DNA-damaging therapeutic agents, p53 acts as a transcription factor to activate subsets of target genes which carry out cell fates such as apoptosis, cell cycle arrest, and DNA repair. Target gene selection by p53 is controlled by a complex regulatory network whose response varies across contexts including treatment type, cell type, and tissue type. The molecular basis of target selection across these contexts is not well understood. Knowledge gained from examining p53 regulatory network profiles across different DNA-damaging agents in different cell types and tissue types may inform logical ways to optimally manipulate the network to encourage p53-mediated tumor suppression and anti-tumor immunity in cancer patients. This may be achieved with combination therapies or with p53-reactivating targeted therapies. Here, we review the basics of the p53 regulatory network in the context of differential responses to DNA-damaging agents; discuss recent efforts to characterize differential p53 responses across treatment types, cell types, and tissue types; and examine the relevance of evaluating these responses in the tumor microenvironment. Finally, we address open questions including the potential relevance of alternative p53 transcriptional functions, p53 transcription-independent functions, and p53-independent functions in the response to DNA-damaging therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms222111828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584119PMC
October 2021

Chitinase 3-like-1 is a therapeutic target that mediates the effects of aging in COVID-19.

JCI Insight 2021 11 8;6(21). Epub 2021 Nov 8.

Molecular Microbiology and Immunology.

COVID-19 is caused by SARS-CoV-2 (SC2) and is more prevalent and severe in elderly and patients with comorbid diseases (CM). Because chitinase 3-like-1 (CHI3L1) is induced during aging and CM, the relationships between CHI3L1 and SC2 were investigated. Here, we demonstrate that CHI3L1 is a potent stimulator of the SC2 receptor angiotensin converting enzyme 2 (ACE2) and viral spike protein priming proteases (SPP), that ACE2 and SPP are induced during aging, and that anti-CHI3L1, kasugamycin, and inhibitors of phosphorylation abrogate these ACE2- and SPP-inductive events. Human studies also demonstrate that the levels of circulating CHI3L1 are increased in the elderly and patients with CM, where they correlate with COVID-19 severity. These studies demonstrate that CHI3L1 is a potent stimulator of ACE2 and SPP, that this induction is a major mechanism contributing to the effects of aging during SC2 infection, and that CHI3L1 co-opts the CHI3L1 axis to augment SC2 infection. CHI3L1 plays a critical role in the pathogenesis of and is an attractive therapeutic target in COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.148749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663553PMC
November 2021

Integrating Molecular Biomarker Inputs Into Development and Use of Clinical Cancer Therapeutics.

Front Pharmacol 2021 19;12:747194. Epub 2021 Oct 19.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States.

Biomarkers can contribute to clinical cancer therapeutics at multiple points along the patient's diagnostic and treatment course. Diagnostic biomarkers can screen or classify patients, while prognostic biomarkers predict their survival. Biomarkers can also predict treatment efficacy or toxicity and are increasingly important in development of novel cancer therapeutics. Strategies for biomarker identification have involved large-scale genomic and proteomic analyses. Pathway-specific biomarkers are already in use to assess the potential efficacy of immunotherapy and targeted cancer therapies. Judicious application of machine learning techniques can identify disease-relevant features from large data sets and improve predictive models. The future of biomarkers likely involves increasing utilization of liquid biopsy and multiple samplings to better understand tumor heterogeneity and identify drug resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.747194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560682PMC
October 2021

Molecular differences between lymph nodes and distant metastases compared with primaries in colorectal cancer patients.

NPJ Precis Oncol 2021 Oct 27;5(1):95. Epub 2021 Oct 27.

Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Lymph nodes (LNs) and distant metastases can arise from independent subclones of the primary tumor. Herein, we characterized the molecular landscape and the differences between LNs, distant metastases and primary colorectal cancers (CRCs). Samples were analyzed using next generation sequencing (NGS, MiSeq on 47 genes, NextSeq on 592 genes) and immunohistochemistry. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. In total, 11,871 samples were examined, comprising primaries (N = 5862), distant (N = 5605) and LNs metastases (N = 404). The most frequently mutated genes in LNs were TP53 (72%), APC (61%), KRAS (39%), ARID1A (20%), PIK3CA (12%). LNs showed a higher mean TMB (13 mut/MB) vs distant metastases (9 mut/MB, p < 0.0001). TMB-high (≥17mut/MB) and MSI-H (8.8% and 6.9% vs 3.7%, p < 0.001 and p = 0.017, respectively) classifications were more frequent in primaries and LNs vs distant metastases (9.5% and 8.8% vs 4.2%, p < 0.001 and p = 0.001, respectively). TMB-high is significantly more common in LNs vs distant metastases and primaries (P < 0.0001), regardless MSI-H status. Overall, LNs showed significantly different rates of mutations in APC, KRAS, PI3KCA, KDM6A, and BRIP1 (p < 0.01) vs primaries, while presenting a distinct molecular profile compared to distant metastases. Our cohort of 30 paired samples confirmed the molecular heterogeneity between primaries, LNs, and distant metastases. Our data support the hypothesis that lymphatic and distant metastases harbor different mutational landscape. Our findings are hypothesis generating and need to be examined in prospective studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41698-021-00230-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551277PMC
October 2021

Antitumorigenic effect of combination treatment with ONC201 and TRAIL in endometrial cancer and .

Cancer Biol Ther 2021 12 25;22(10-12):554-563. Epub 2021 Oct 25.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA.

ONC201 demonstrated promising activity in patients with advanced endometrial cancer in a Phase I clinical trial. ONC201 activates the integrated stress response (ISR) and upregulates TRAIL and its receptor DR5. We hypothesized ONC201 upregulation of DR5 could sensitize tumors to TRAIL and combination of ONC201 and TRAIL would lead to enhanced cell death in endometrial cancer models. Five endometrial cancer cell lines AN3CA, HEC1A, Ishikawa, RL952, and KLE as well as a murine xenograft model were treated with ONC201 alone or in combination with TRAIL. ONC201 decreased the cell viability of all five endometrial cancer cell lines at clinically achievable low micro-molar concentrations (2-4 μM). ONC201 activated the ISR and induced protein expression of TRAIL and DR5 at the cell surface. Pretreatment with ONC201 sensitized endometrial cancer cell lines to TRAIL, leading to increased cell death induction compared to either agent alone. Tumor growth was reduced by the ONC201/TRAIL combination treatment in the xenograft model of endometrial cancer ( = .014). Mice treated with combination treatment survived significantly longer than mice from the three control groups ( = .018). ONC201 decreased cell viability in endometrial cancer cells lines primarily through growth arrest while the combination of ONC201 and TRAIL promoted cell death and . Our results suggest a novel cancer therapeutic strategy that can be further investigated in the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15384047.2021.1977067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726732PMC
December 2021

Anti-cancer efficacy including Rb-deficient tumors and VHL-independent HIF1α proteasomal destabilization by dual targeting of CDK1 or CDK4/6 and HSP90.

Sci Rep 2021 10 22;11(1):20871. Epub 2021 Oct 22.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, USA.

A prevalent characteristic of solid tumors is intra-tumoral hypoxia. Hypoxia-inducible factor 1α (HIF1α) predominantly mediates the adaptive response to O oscillation and is linked to multiple malignant hallmarks. Here we describe a strategy to robustly target HIF1α by dual inhibition of CDK(s) and heat shock protein 90 (HSP90). We show that CDK1 may contribute to HSP90-mediated HIF1α stabilization. CDK1 knockdown enhances the decrease of HIF1α by HSP90 inhibition. Dual inhibition of CDK1 and HSP90 significantly increases apoptosis and synergistically inhibits cancer cell viability. Similarly, targeting CDK4/6 using FDA-approved inhibitors in combination with HSP90 inhibition shows a class effect on HIF1α inhibition and cancer cell viability suppression not only in colorectal but also in various other cancer types, including Rb-deficient cancer cells. Dual inhibition of CDK4/6 and HSP90 suppresses tumor growth in vivo. In summary, combined targeting of CDK(s) (CDK1 or CDK4/6) and HSP90 remarkably inhibits the expression level of HIF1α and shows promising anti-cancer efficacy with therapeutic potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-00150-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536770PMC
October 2021

Hyperprogression of a mismatch repair-deficient colon cancer in a humanized mouse model following administration of immune checkpoint inhibitor pembrolizumab.

Oncotarget 2021 Oct 12;12(21):2131-2146. Epub 2021 Oct 12.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School of Brown University, Providence, RI, USA.

Immunotherapy is an established treatment modality in oncology. However, in addition to primary or acquired therapy resistance with immune checkpoint blockade (ICB), hyperprogressive disease (HPD) or hyperprogression (HP) with acceleration of tumor growth occurs in a subset of patients receiving ICB therapy. A validated and predictive animal model would help investigate HPD/HP to develop new approaches for this challenging clinical entity. Using human cytotoxic T-cell line TALL-104 injected intraperitoneally into immunodeficient NCRU-nude athymic mice bearing mismatch repair-deficient (MMR-d) human colon carcinoma HCT116 p53-null (but not wild-type p53) tumor xenograft, we observed accelerated tumor growth after PD-1 blockade with pembrolizumab administration. There was increased colon tumor cell proliferation as determined by immunohistochemical Ki67 staining of tumor sections. There was no increase in MDM2 or MDM4/MDMX in the p53-null HCT116 cells versus the wild-type p53-expressing isogenic tumor cells, suggesting the effects in this model may be MDM2 or MDM4/MDMX-independent. Human cytokine profiling revealed changes in IFN-γ, TRAIL-R2/TNFRSF10B, TRANCE/TNFSF11/RANK L, CCL2/JE/MCP-1, Chitinase 3-like 1, IL-4 and TNF-α. This represents a novel humanized HPD mouse model with a link to deficiency of the p53 pathway of tumor suppression in the setting of MMR-d. Our novel humanized preclinical TALL-104/p53-null HCT116 mouse model implicates p53-deficiency in an MMR-d tumor as a possible contributor to HPD/HP and may help with evaluating therapeutic strategies in cancer immunotherapy to extend clinical benefits of ICB's in a broader patient population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.28086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522841PMC
October 2021

Potent preclinical sensitivity to imipridone-based combination therapies in oncohistone H3K27M-mutant diffuse intrinsic pontine glioma is associated with induction of the integrated stress response, TRAIL death receptor DR5, reduced ClpX and apoptosis.

Am J Cancer Res 2021 15;11(9):4607-4623. Epub 2021 Sep 15.

Joint Program in Cancer Biology, Brown University and Lifespan Cancer Institute USA.

The H3K27M oncohistone mutation, identified in approximately 80% of diffuse intrinsic pontine gliomas (DIPG), is a potential target for therapy. Imipridone ONC201/TIC10 (TRAIL-Inducing Compound #10) induces apoptosis of cancer cells, and has clinical efficacy against H3K27M-mutant DIPG. We demonstrate synergy between ONC201, ONC206 and ONC212, and targeted therapies with known preclinical activity against DIPG. We hypothesized that imipridone combinations with HDAC or proteasome inhibitors may be superior to single agent ONC201 treatment in H3K27M mutant DIPG. Six patient-derived DIPG cell lines (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SU-DIPG-27, SU-DIPG-29, SU-DIPG-36) were exposed to imipridones alone or combinations with histone de-acetylase inhibitors [HDACi], marizomib, etoposide, and temozolomide. Dose-dependent response to imipridones was observed in DIPG cells with half-maximal inhibitory concentration (IC) of 1.46 µM, 0.11 µM, and 0.03 µM, for ONC201, ONC206, and ONC212, respectively. Upon treatment with the imipridones, DIPG cell lines engaged CLpP/CLPX, the integrated stress response with ATF4 activation, and TRAIL death receptor 5 (DR5) induction. Strong synergy was identified between ONC201 and HDACi panobinostat (combination index [CI] 0.01), romidepsin (CI 0.08) and proteasome inhibitor marizomib (CI 0.19). Synergy was demonstrated between ONC201 and etoposide (CI 0.54), although to a lesser degree than with panobinostat, romidepsin, and marizomib. ONC206 and ONC212 showed similar synergistic effects with panobinostat, romidepsin, and marizomib. Induction of apoptosis was demonstrated with imipridones and panobinostat or romidepsin combinations. Our results suggest increased sensitivity of H3K27M-mutant DIPG cell lines to second generation imipridone therapies, as compared to ONC201. Additionally, there is synergistic cell death with combination of imipridones and panobinostat, romidepsin, or marizomib, which may be further tested and in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493379PMC
September 2021

Targeting the Integrated Stress Response in Cancer Therapy.

Front Pharmacol 2021 24;12:747837. Epub 2021 Sep 24.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States.

The integrated stress response (ISR) is an evolutionarily conserved intra-cellular signaling network which is activated in response to intrinsic and extrinsic stresses. Various stresses are sensed by four specialized kinases, PKR-like ER kinase (PERK), general control non-derepressible 2 (GCN2), double-stranded RNA-dependent protein kinase (PKR) and heme-regulated eIF2α kinase (HRI) that converge on phosphorylation of serine 51 of eIF2α. eIF2α phosphorylation causes a global reduction of protein synthesis and triggers the translation of specific mRNAs, including activating transcription factor 4 (ATF4). Although the ISR promotes cell survival and homeostasis, when stress is severe or prolonged the ISR signaling will shift to regulate cellular apoptosis. We review the ISR signaling pathway, regulation and importance in cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.747837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498116PMC
September 2021

Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells.

Oncotarget 2021 Sep 28;12(20):2006-2021. Epub 2021 Sep 28.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.

Colorectal cancer (CRC) caused over 900,000 deaths worldwide in 2020. A majority of late-stage CRC patients are treated with 5-fluorouracil (5-FU) combined with either irinotecan (CPT-11), oxaliplatin, or both. Despite their widespread use, the mechanisms of efficacy and toxicity of these drugs remain incompletely understood. While previous work has investigated cellular responses to these agents individually, we directly compare the transcriptomic and cytokine profiles of HCT116 wild-type and p53-/- colorectal cancer cells treated with these drugs and report pan-drug, drug-specific, drug class-specific, p53-independent, and p53-dependent signatures. We observed downregulation of histone genes by 5-FU (that significantly correlates with improved survival in CRC patients) and upregulation of FOS and ATF3 by oxaliplatin (which may contribute to peripheral neuropathy). BTG2 was identified as a top gene upregulated by all four drugs, suggesting its critical role in the cellular response to chemotherapy in CRC. Soluble TRAILR2 (death receptor 5; DR5) is a decoy receptor for TRAIL, an apoptosis-inducing cytokine. TRAILR2 was down-regulated by oxaliplatin and 5-FU, was not affected by CPT-11, and was increased by cisplatin. There was an increase in IL-8 by oxaliplatin and increase in ferritin by cisplatin which may contribute to cancer cell survival. Novel drug-specific mechanisms of efficacy or toxicity identified in these signatures may be targeted with combination therapies or development of new targeted therapies. Together, the findings here contribute to our understanding of the molecular bases of efficacy and toxicity of chemotherapeutic agents often used for treatment of GI cancer such as CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.28075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487728PMC
September 2021

Opposing effects of BRCA1 mRNA expression on patient survival in breast and colorectal cancer and variations among African American, Asian, and younger patients.

Oncotarget 2021 Sep 28;12(20):1992-2005. Epub 2021 Sep 28.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.

Breast cancer (BC) and colorectal cancer (CRC) are common and show poor survival in advanced stages. Using The Cancer Genome Atlas (TCGA) computational tool cBioPortal, we evaluated overall patient survival in BRCA1 mRNA-low versus -high cohorts (<-1.29 versus >1.05 SD from mean BRCA1 expression, respectively). Analysis included 1082 BC patients with mRNA data (PanCancer Atlas), 382 CRCs (Firehose Legacy) and 592 CRCs (PanCancer Atlas). As previously reported, BRCA1 mRNA-low tumor expression positively correlated with BC patient survival but was negatively associated in CRC. We observed a correlation between BRCA1 mRNA-high and age <45 years at CRC diagnosis using a Fisher's exact test [Firehose Legacy database (-value = 0.0091); CRC PanCancer Atlas (-value = 0.0778)]. We correlated BRCA1 mRNA-low expression and basal BC (-value = 0.0016) and BRCA1 mRNA-low tumors and frequency of African American patients (-value = 0.0448) with BC. Other trends included higher frequency of advanced lymph node stage and mucinous adenocarcinoma among BRCA1 mRNA-low CRC and higher frequency of males in BRCA1 mRNA-high BC and CRC. African Americans more frequently had BRCA1 mRNA-low BC and BRCA1 mRNA-high CRC and the opposite was observed among Asians. Using a gene co-expression tool (cBioPortal), we observed TOP2A and ATAD5 levels correlate (Spearman's correlation>0.6) with BRCA1 in BC and CRC, whereas LMNB2 correlates with BRCA1 in CRC, suggesting tissue-specific BRCA1 interactions. Our results indicate potential for BRCA1 mRNA expression levels as a prognostic biomarker in BC and CRC, suggest tissue-specificity in BRCA1 molecular interactions, and point to BRCA1 mRNA-high levels as a characteristic of CRC tumors in younger versus older individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.28082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487727PMC
September 2021

A high-throughput customized cytokinome screen of colon cancer cell responses to small-molecule oncology drugs.

Oncotarget 2021 Sep 28;12(20):1980-1991. Epub 2021 Sep 28.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.

Inflammatory cytokines, chemokines, and growth factors are molecular messengers that circulate and have the capability to modify the tumor microenvironment and impact therapeutic response. The characterization of soluble mediators as biomarkers for diagnosis and prognosis is of interest in oncology. We utilize the cytokinome to characterize the response of colorectal tumor cell lines to selected small-molecules in oncology as a proof-of-concept dataset with immunomodulatory analyte heat map rankings for drug and cell line combinations. We observed overall trends in drug class effects with MEK-, BRAF-, PARP-inhibitors, and Imipridones in cytokine, chemokine, and growth factor responses that may help guide therapy selection. MEK-inhibitor treatment downregulated analytes VEGF, CXCL9/MIG, and IL-8/CXCL8 and upregulated CXCL14/BRAK, Prolactin, and CCL5/RANTES. BRAF-inhibitor treatment downregulated VEGF and IL-8/CXCL8, while increasing soluble TRAIL-R2. Treatment with PARP-inhibitors decreased CXCL9/MIG, IL-8/CXCL8, CCL3/MIP-1 alpha, VEGF, and CXCL14/BRAK, while treatment increased soluble TRAIL-R2 and prolactin. Treatment with Imipridones decreased CCL3/MIP-1 alpha, VEGF, CXCL14/BRAK, IL-8/CXCL8, and Prolactin and increased CXCL5/ENA-78. We also observed differential responses to therapeutics depending on the mutational profile of the cell line. In the future, a similar but larger dataset may be utilized in the clinic to aid in the prediction of patient response to immunomodulatory therapies based on tumor genotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.28079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487726PMC
September 2021
-->