5 results on '"Rajanala, Sai Harisha"'
Search Results
2. Quantifying Y chromosome loss in primary and metastatic prostate cancer by chromosome painting.
- Author
-
Rajanala, Sai Harisha, Ghale, Romina, Nandakumar, Subhiksha, Chadalavada, Kalyani, Lee, Gwo-Shu Mary, Stopsack, Konrad H., Chen, Yu, Nanjangud, Gouri J., Chakraborty, Goutam, and Kantoff, Philip W.
- Subjects
- *
Y chromosome , *CASTRATION-resistant prostate cancer , *PROSTATE cancer , *METASTASIS , *CHROMOSOMES , *NUDITY - Abstract
Somatic Y chromosome loss in hematopoietic cells is associated with higher mortality in men. However, the status of the Y chromosome in cancer tissue is not fully known due to technical limitations, such as difficulties in labelling and sequencing DNA from the Y chromosome. We have developed a system to quantify Y chromosome gain or loss in patient-derived prostate cancer organoids. Using our system, we observed Y chromosome loss in 4 of the 13 (31%) patient-derived metastatic castration-resistant prostate cancer (mCRPC) organoids; interestingly, loss of Yq (long arm of the Y chromosome) was seen in 38% of patient-derived organoids. Additionally, potential associations were observed between mCRPC and Y chromosome nullisomy. The prevalence of Y chromosome loss was similar in primary and metastatic tissue, suggesting that Y chromosome loss is an early event in prostate cancer evolution and may not a result of drug resistance or organoid derivation. This study reports quantification of Y chromosome loss and gain in primary and metastatic prostate cancer tissue and lays the groundwork for further studies investigating the clinical relevance of Y chromosome loss or gain in mCRPC. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. SLCO1B3 and SLCO2B1 genotypes, androgen deprivation therapy, and prostate cancer outcomes: a prospective cohort study and meta-analysis.
- Author
-
Rajanala, Sai Harisha, Plym, Anna, Vaselkiv, Jane B, Ebot, Ericka M, Matsoukas, Konstantina, Lin, Zhike, Chakraborty, Goutam, Markt, Sarah C, Penney, Kathryn L, Lee, Gwo-Shu M, Mucci, Lorelei A, Kantoff, Philip W, and Stopsack, Konrad H
- Abstract
Solute carrier organic anion (SLCO) transporters (OATP transporters) are involved in cellular uptake of drugs and hormones. Germline variants in SLCO1B3 and SLCO2B1 have been implicated in prostate cancer progression and therapy response, including to androgen deprivation and statin medications, but results have appeared heterogeneous. We conducted a cohort study of five single-nucleotide polymorphisms (SNPs) in SLCO1B3 and SLCO2B1 with prior evidence among 3208 men with prostate cancer who participated in the Health Professionals Follow-up Study or the Physicians' Health Study, following participants prospectively after diagnosis over 32 years (median, 14 years) for development of metastases and cancer-specific death (lethal disease, 382 events). Results were suggestive of, but not conclusive for, associations between some SNPs and lethal disease and differences by androgen deprivation and statin use. All candidate SNPs were associated with SLCO mRNA expression in tumor-adjacent prostate tissue. We also conducted a systematic review and harmonized estimates for a dose-response meta-analysis of all available data, including 9 further studies, for a total of 5598 patients and 1473 clinical events. The A allele of the exonic SNP rs12422149 (14% prevalence), which leads to lower cellular testosterone precursor uptake via SLCO2B1, was associated with lower rates of prostate cancer progression (hazard ratio per A allele, 0.80; 95% confidence interval, 0.69–0.93), with little heterogeneity between studies (I 2, 0.27). Collectively, the totality of evidence suggests a strong association between inherited genetic variation in SLCO2B1 and prostate cancer prognosis, with potential clinical use in risk stratification related to androgen deprivation therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
4. Increased MYBL2 expression in aggressive hormone‐sensitive prostate cancer.
- Author
-
Yoshikawa, Yuki, Stopsack, Konrad H., Wang, Xin Victoria, Chen, Yu‐Hui, Mazzu, Ying Z., Burton, Foster, Chakraborty, Goutam, Rajanala, Sai Harisha, Hirani, Rahim, Nandakumar, Subhiksha, Lee, Gwo‐Shu Mary, Frank, David, Davicioni, Elai, Liu, Glenn, Carducci, Michael A., Azuma, Haruhito, Kantoff, Philip W., and Sweeney, Christopher J.
- Abstract
Loss of the histone demethylase KDM5D (lysine‐specific demethylase 5D) leads to in vitro resistance of prostate cancer cells to androgen deprivation therapy (ADT) with and without docetaxel. We aimed to define downstream drivers of the KDM5D effect. Using chromatin immunoprecipitation sequencing (ChIP‐seq) of the LNCaP cell line (androgen‐sensitive human prostate adenocarcinoma) with and without silenced KDM5D, MYBL2‐binding sites were analyzed. Associations between MYBL2 mRNA expression and clinical outcomes were assessed in cohorts of men with localized and metastatic hormone‐sensitive prostate cancer. In vitro assays with silencing and overexpression of MYBL2 and KDM5D in androgen receptor (AR)‐positive hormone‐sensitive prostate cancer cell lines, LNCaP and LAPC4, were used to assess their influence on cellular proliferation, apoptosis, and cell cycle distribution, as well as sensitivity to androgen deprivation, docetaxel, and cabazitaxel. We found that silencing KDM5D increased histone H3 lysine K4 (H3K4) trimethylation and increased MYBL2 expression. KDM5D and MYBL2 were negatively correlated with some but not all clinical samples. Higher MYBL2 expression was associated with a higher rate of relapse in localized disease and poorer overall survival in men with metastatic disease in the CHAARTED trial. Lower MYBL2 levels enhanced LNCaP and LAPC4 sensitivity to androgen deprivation and taxanes. In vitro, modifications of KDM5D and MYBL2 altered cell cycle distribution and apoptosis in a cell line‐specific manner. These results show that the transcription factor MYBL2 impacts in vitro hormone‐sensitive prostate cancer sensitivity to androgen deprivation and taxanes, and lower levels are associated with better clinical outcomes in men with hormone‐sensitive prostate cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
5. The Impact of PIK3R1 Mutations and Insulin-PI3K-Glycolytic Pathway Regulation in Prostate Cancer.
- Author
-
Chakraborty G, Nandakumar S, Hirani R, Nguyen B, Stopsack KH, Kreitzer C, Rajanala SH, Ghale R, Mazzu YZ, Pillarsetty NVK, Lee GM, Scher HI, Morris MJ, Traina T, Razavi P, Abida W, Durack JC, Solomon SB, Vander Heiden MG, Mucci LA, Wibmer AG, Schultz N, and Kantoff PW
- Subjects
- Class Ia Phosphatidylinositol 3-Kinase genetics, Glycolysis, Humans, Insulin genetics, Insulin metabolism, Male, Mutation, Positron Emission Tomography Computed Tomography, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Prostatic Neoplasms genetics
- Abstract
Purpose: Oncogenic alterations of the PI3K/AKT pathway occur in >40% of patients with metastatic castration-resistant prostate cancer, predominantly via PTEN loss. The significance of other PI3K pathway components in prostate cancer is largely unknown., Experimental Design: Patients in this study underwent tumor sequencing using the MSK-IMPACT clinical assay to capture single-nucleotide variants, insertions, and deletions; copy-number alterations; and structural rearrangements, or were profiled through The Cancer Genome Atlas. The association between PIK3R1 alteration/expression and survival was evaluated using univariable and multivariable Cox proportional-hazards regression models. We used the siRNA-based knockdown of PIK3R1 for functional studies. FDG-PET/CT examinations were performed with a hybrid positron emission tomography (PET)/CT scanner for some prostate cancer patients in the MSK-IMPACT cohort., Results: Analyzing 1,417 human prostate cancers, we found a significant enrichment of PIK3R1 alterations in metastatic cancers compared with primary cancers. PIK3R1 alterations or reduced mRNA expression tended to be associated with worse clinical outcomes in prostate cancer, particularly in primary disease, as well as in breast, gastric, and several other cancers. In prostate cancer cell lines, PIK3R1 knockdown resulted in increased cell proliferation and AKT activity, including insulin-stimulated AKT activity. In cell lines and organoids, PIK3R1 loss/mutation was associated with increased sensitivity to AKT inhibitors. PIK3R1-altered patient prostate tumors had increased uptake of the glucose analogue 18F-fluorodeoxyglucose in PET imaging, suggesting increased glycolysis., Conclusions: Our findings describe a novel genomic feature in metastatic prostate cancer and suggest that PIK3R1 alteration may be a key event for insulin-PI3K-glycolytic pathway regulation in prostate cancer., (©2022 American Association for Cancer Research.)
- Published
- 2022
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.