A5006632634- Cancer-related Molecular Pathways
- Cancer, Hypoxia, and Metabolism
- Cancer therapeutics and mechanisms
- Cell death mechanisms and regulation
- MicroRNA in disease regulation
- Epigenetics and DNA Methylation
- Prostate Cancer Treatment and Research
- PARP inhibition in cancer therapy
- Cancer Genomics and Diagnostics
- Cancer Mechanisms and Therapy
- RNA modifications and cancer
- Genetic factors in colorectal cancer
- Cancer Cells and Metastasis
- interferon and immune responses
- Cancer Treatment and Pharmacology
- Lung Cancer Treatments and Mutations
- Cancer, Lipids, and Metabolism
- Ubiquitin and proteasome pathways
- Advanced Breast Cancer Therapies
- FOXO transcription factor regulation
- Mitochondrial Function and Pathology
- CRISPR and Genetic Engineering
- Mass Spectrometry Techniques and Applications
- Pancreatic function and diabetes
- Lung Cancer Research Studies
Fox Chase Cancer Center
2016-2022
Lifespan
2021
Brown University
2021
Translational Research in Oncology
2017
We have developed 3D-tumoroids and tumor slice in vitro culture systems from surgical specimens derived patients with colorectal cancer (CRC) or lung to evaluate immune cell populations infiltrating cultured tissues. The system incorporates patient's peripherally tumor-derived cells into tumoroid cultures the ability of mimic an immunosuppressive microenvironment (ITM). This enables analysis response standard therapy within weeks resection. Here we show that a CRC patient are highly...
Anti-cancer small molecule ONC201 upregulates the integrated stress response (ISR) and acts as a dual inactivator of Akt/ERK, leading to TRAIL gene activation. is under investigation in multiple clinical trials treat patients with cancer. Given unique imipridone core chemical structure ONC201, we synthesized series analogs identify additional compounds distinct therapeutic properties. Several imipridones broad range vitro potencies were identified an exploration derivatives. Based on potency...
CDK4/6 targeting is a promising therapeutic strategy under development for various tumor types. In this study, we used computational methods and The Cancer Genome Atlas dataset analysis to identify novel miRNAs that target exhibit potential in colorectal cancer. 3'UTR of mRNAs are targeted by family miRNAs, which includes miR-6883-5p, miR-149*, miR-6785-5p, miR-4728-5p. Ectopic expression miR-6883-5p or miR-149* downregulated CDK4 CDK6 levels human cancer cells. RNA-seq revealed an inverse...
Pancreatic cancer is chemo-resistant and metastasizes early with an overall five-year survival of ∼8.2%. First-in-class imipridone ONC201 a small molecule in clinical trials anti-cancer activity. ONC212, fluorinated-ONC201 analogue, shows preclinical efficacy melanoma hepatocellular-cancer models. We investigated ONC212 against pancreatic cell lines (N=16 including 9 PDX-cell lines). demonstrate 4 in-vivo models ONC201-resistant tumors. active as single agent or combination 5-fluorouracil,...
Cancer stem cells (CSCs) correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone Phase I/II for advanced cancer. We previously shown that targets self-renewing, chemotherapy-resistant colorectal via Akt/ERK inhibition DR5/TRAIL induction. In this study, we demonstrate the anti-CSC effects involve early changes...
// Safoora Deihimi 1,2,3,7 , Avital Lev 1,2,3 Michael Slifker 4 Elena Shagisultanova 3,9 Qifang Xu 2 Kyungsuk Jung 5 Namrata Vijayvergia 3 Eric A. Ross 4,6 Joanne Xiu 8 Jeffrey Swensen Zoran Gatalica Mark Andrake Roland L. Dunbrack and Wafik S. El-Deiry 1 Laboratory of Translational Oncology Experimental Cancer Therapeutics, Fox Chase Center, Philadelphia, PA, USA Molecular Therapeutics Program, Department Hematology/Oncology, Biostatistics Bioinformatics Department, Medicine, 6 Prevention...
Abstract Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most cancers eventually become androgen-independent resistant to ADT progressing metastatic castration-resistant (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance AR-targeted the progression mCRPC, they represent an important...
// Marie D. Ralff 1 , 2 Aakash Jhaveri 3 4 5 Jocelyn E. Ray 6 Lanlan Zhou 10 Avital Lev Kerry S. Campbell 7 David T. Dicker Eric A. Ross 8 and Wafik El-Deiry 9 MD/PhD Program, The Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA Laboratory Translational Oncology Experimental Cancer Therapeutics, Department Medical Molecular Therapeutics Fox Chase Center, Master Science in Biotechnology Warren Alpert School, Brown Providence, RI, Joint Program Biology, University the...
A long-term goal in the cancer-field has been to develop strategies for treating p53-mutated tumors. novel small-molecule, PG3-Oc, restores p53 pathway-signaling tumor cells with mutant-p53, independently of p53/p73. PG3-Oc partially upregulates p53-transcriptome (13.7% public target-gene dataset; 15.2% in-house dataset) and p53-proteome (18%, HT29; 16%, HCT116-p53-/-). Bioinformatic analysis indicates critical p53-effectors growth-arrest (p21), apoptosis (PUMA, DR5, Noxa), autophagy...
Abstract A prevalent characteristic of solid tumors is intra-tumoral hypoxia. Hypoxia-inducible factor 1α (HIF1α) predominantly mediates the adaptive response to O 2 oscillation and linked multiple malignant hallmarks. Here we describe a strategy robustly target HIF1α by dual inhibition CDK(s) heat shock protein 90 (HSP90). We show that CDK1 may contribute HSP90-mediated stabilization. knockdown enhances decrease HSP90 inhibition. Dual significantly increases apoptosis synergistically...
Mutations in TP53 occur commonly the majority of human tumors and confer aggressive tumor phenotypes, including metastasis therapy resistance. CB002 structural-analogs restore p53 signaling with mutant-p53 but we find that unlike other xanthines such as caffeine, pentoxifylline, theophylline, they do not deregulate G2 checkpoint. Novel CB002-analogs induce pro-apoptotic Noxa protein an ATF3/4-dependent manner, whereas theophylline not. By contrast to target S-phase checkpoint associated...
Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the United States. We analyzed 26 MSI-High and 558 non-MSI-High CRC tumors. BRCA2 mutations were highly enriched (50%) CRC. Immunohistochemistry showed that BRCA2-mutated had high c-MET (64%) expression compared with BRCA-WT (17%). hypothesized mechanistic link between BRCA2-deficiency overexpression synergistic interaction drugs treat BRCA-deficient tumors (mitomycin C (MMC) or PARP inhibitors) inhibitors (crizotinib)....
Abstract The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or anti-angiogenesis processes. Over 50% of human cancers harbor cancer-causing mutations in p53. not only abrogate its function, but also endow mutant with a gain function (GOF), creating proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- radiotherapy resistance. Thus, targeting and/or restoring wild-type signaling pathway provides an attractive...
Abstract ONC201 was initially identified as an inducer of cell death through the tumor necrosis factor related apoptosis inducing ligand (TRAIL) pathway. The compound is being tested in patients with a variety types, including those breast. Both triple negative breast cancer (TNBC) cells and non-TNBC are sensitive to ONC201. In subset TRAIL-sensitive TNBC cells, treatment leads induction TRAIL-dependent manner. majority TRAIL-resistant ONC201’s effects anti-proliferative rather than...
Abstract A long-term goal in the cancer-field has been to develop strategies for treating p53-mutated tumors. novel small-molecule, PG3-Oc, restores p53 pathway-signaling tumor cells with mutant-p53, independently of p53/p73. PG3-Oc partially upregulates p53-transcriptome (13.7% public target-gene dataset; 15.2% in-house dataset) and p53-proteome (18%, HT29; 16%, HCT116-p53 -/- ). Bioinformatic analysis indicates critical p53-effectors growth-arrest (p21), apoptosis (PUMA, DR5, Noxa),...
ONC201 was initially identified as an inducer of cell death through the tumor necrosis factor related apoptosis inducing ligand (TRAIL) pathway. The compound is being tested in patients with a variety types, including those breast. Both triple negative breast cancer (TNBC) cells and non-TNBC are sensitive to ONC201. In subset TRAIL-sensitive TNBC cells, treatment leads induction TRAIL-dependent manner. majority TRAIL-resistant ONC201's effects anti-proliferative rather than apoptotic. vivo,...
Abstract ONC201 is a first-in-class anti-tumor agent that selectively targets cancer cells without observed toxicity. being tested in phase I/II clinical trials for patients with advanced solid tumors and hematological malignancies. Several contain rare population of stem (CSCs) capable self-renewal contribute to tumor maintenance resistance therapy. We have previously demonstrated self-renewing, chemotherapy-resistant colorectal CSCs (Prabhu et al, Cancer Res, 2015). hypothesized anti-CSC...
Abstract Pancreatic cancer is a highly chemo-resistant tumor type known to aggressively metastasize at an early stage with overall five-year survival rate of ~6%. In this study we tested the efficacy ONC201 and ONC212 in panel pancreatic cell lines patient-derived models vitro vivo. founding member imipridone class small molecules anti-proliferative pro-apoptotic effects various types. Kline et al. Allen previously showed that stimulates integrated stress response by up-regulating ATF4, CHOP...
Abstract Androgen receptor (AR) signaling plays a key role in prostate cancer progression; thus Deprivation Therapy (ADT) is mainstay therapy for patients with advanced cancer. However, most cases the tumor becomes androgen-independent and resistant to ADT ultimately progressing metastatic castration (mCRPC). Constitutively activated AR splice variants (AR-Vs) have emerged as major mediators of resistance AR-targeted progression mCRPC, representing an important therapeutic target mCRPC. Out...
Abstract Most cancers harbor intra-tumoral hypoxia which promotes tumor progression and therapy resistance. Hypoxia-inducible factor 1α (HIF1α) mediates an adaptive response to contributes multiple cancer hallmarks. We describe therapeutic targeting of HIF1α by combination CDK4/6 inhibitors (CDK4/6i) heat-shock protein 90 (HSP90i). CDK1 HSP90-mediated stabilization whereas CDK1-knockdown enhances reduction HSP90i. Dual CDK1- HSP90-inhibition increases apoptosis synergistically inhibits cell...