Project description:The purpose of this study was to develop better ways of detecting prostate cancer before and after pre-operative treatment, and to test the feasibility of multi parametric magnetic resonance imaging (mpMRI) for the localization and detection of focal prostate cancer both before and after pre-operative treatment with ADT and enzalutamide. In this study, patients with intermediate and high risk prostate cancer received six months of neoadjuvant intense androgen deprivation therapy prior to radical prostatectomy. Biopsies were acquired prior to treatment. Tissue from biopsy and radical prostatectomy were subjected to sequencing and analysis for determination of features associated with response or resistance to treatment.
Project description:Androgen deprivation therapy (ADT) is a cornerstone treatment for locally advanced or metastatic prostate cancer (PCa). However, its potential effects on the tumor immune microenvironment (TIM) of PCa patients and the underlying mechanism remain largely unclear.We used RNA sequencing to reveal the effects of ADT on the PCa TIM at the transcriptome level. RNA sequencing was performed on 6 paired pre-ADT biopsy and post-ADT PCa lesions and 5 paired paracancerous benign tissues from patients receiving neoadjuvant ADT with locally advanced PCa.
Project description:Plasma proteomics (LC-MS/MS) was performed on samples from 40 esophageal squamous cell carcinoma patients undergoing neoadjuvant therapy (neoadjuvant immuno-chemotherapy or neoadjuvant chemotherapy). Samples were collected at baseline and at the end of therapy to investigate proteomic differences associated with treatment response.
Project description:Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations.
Project description:Phosphodiesterase 10A (PDE10) was previously reported to be overexpressed in various cancers and essential for cancer cell proliferation and survival. Here, we studied a novel PDE10 inhibitor, ADT-030, and found it to potently and selectively inhibit KRAS mutant PDAC cell proliferation and clonogenicity by inducing G2/M arrest and apoptosis. ADT-030 also inhibited migration. These effects were mediated by increased cAMP/cGMP levels and activation of PKA/PKG. The growth inhibitory activity of ADT-030 was associated with reduced β-catenin and RAS signaling. Notably, ADT-030 also inhibited the growth of KRASG12D and KRASG12C mutant PDAC cells resistant to allele-specific KRAS inhibitors. Oral administration of ADT-030 significantly suppressed tumor growth, reduced lung and liver metastasis, and increased survival without systemic toxicity in syngeneic and patient-derived xenograft (PDX) models. ADT-030 also increased chemotherapy response in orthotopic PDAC models. Immune phenotyping and single cell RNA revealed remodeling by ADT-030 with a more favorable immune suppressive tumor immune microenvironment to activate anti-tumor immunity. These results show that ADT-030 is a promising drug development candidate capable of simultaneously targeting key oncogenic signaling pathways, resulting in tumor-intrinsic and immunomodulatory effects for the treatment of KRAS-mutant PDAC.
Project description:Purpose: The goals of this study is to compare NGS-derived Androgen Deprivation Therapy (ADT) resistant miRNome profiling to Androgen Deprivation Therapy (ADT) sensitive miRNome profile in African American prostate cancer cells and validate by reverse transcription polymerase chain reaction (qRT–PCR) methods. Method: Mirco-RNA were isolated from different CaP cells who were sensitive and resistant to Androgen Deprivation Therapy (ADT). Total micro-RNA were subjected to miRNA-Seq. Results: We performed whole miRNA-Seq analysis through paired-end deep sequencing to systematically investigate the molecular features of different CaP cell models- RC-77-N, RC-77T/E, RCC7T/E-ADT, RCC7T/E-CD133-plus, E006AA-hT and E006AA-hT-ADT. Conclusions: Our study represents the first detailed analysis of African American ADT resistant miRNome, with biologic replicates, generated by miRNA-seq technology.