Browsing by Author "Gupta, Santosh"
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Item Open Access Characterization of a castrate-resistant prostate cancer xenograft derived from a patient of West African ancestry.(Prostate cancer and prostatic diseases, 2021-10-13) Patierno, Brendon M; Foo, Wen-Chi; Allen, Tyler; Somarelli, Jason A; Ware, Kathryn E; Gupta, Santosh; Wise, Sandra; Wise, John P; Qin, Xiaodi; Zhang, Dadong; Xu, Lingfan; Li, Yanjing; Chen, Xufeng; Inman, Brant A; McCall, Shannon J; Huang, Jiaoti; Kittles, Rick A; Owzar, Kouros; Gregory, Simon; Armstrong, Andrew J; George, Daniel J; Patierno, Steven R; Hsu, David S; Freedman, Jennifer ABackground
Prostate cancer is a clinically and molecularly heterogeneous disease, with highest incidence and mortality among men of African ancestry. To date, prostate cancer patient-derived xenograft (PCPDX) models to study this disease have been difficult to establish because of limited specimen availability and poor uptake rates in immunodeficient mice. Ancestrally diverse PCPDXs are even more rare, and only six PCPDXs from self-identified African American patients from one institution were recently made available.Methods
In the present study, we established a PCPDX from prostate cancer tissue from a patient of estimated 90% West African ancestry with metastatic castration resistant disease, and characterized this model's pathology, karyotype, hotspot mutations, copy number, gene fusions, gene expression, growth rate in normal and castrated mice, therapeutic response, and experimental metastasis.Results
This PCPDX has a mutation in TP53 and loss of PTEN and RB1. We have documented a 100% take rate in mice after thawing the PCPDX tumor from frozen stock. The PCPDX is castrate- and docetaxel-resistant and cisplatin-sensitive, and has gene expression patterns associated with such drug responses. After tail vein injection, the PCPDX tumor cells can colonize the lungs of mice.Conclusion
This PCPDX, along with others that are established and characterized, will be useful pre-clinically for studying the heterogeneity of prostate cancer biology and testing new therapeutics in models expected to be reflective of the clinical setting.Item Open Access LRP1B mutations are associated with favorable outcomes to immune checkpoint inhibitors across multiple cancer types.(Journal for immunotherapy of cancer, 2021-03) Brown, Landon C; Tucker, Matthew D; Sedhom, Ramy; Schwartz, Eric B; Zhu, Jason; Kao, Chester; Labriola, Matthew K; Gupta, Rajan T; Marin, Daniele; Wu, Yuan; Gupta, Santosh; Zhang, Tian; Harrison, Michael R; George, Daniel J; Alva, Ajjai; Antonarakis, Emmanuel S; Armstrong, Andrew JBackground
Low-density lipoprotein receptor-related protein 1b (encoded by LRP1B) is a putative tumor suppressor, and preliminary evidence suggests LRP1B-mutated cancers may have improved outcomes with immune checkpoint inhibitors (ICI).Methods
We conducted a multicenter, retrospective pan-cancer analysis of patients with LRP1B alterations treated with ICI at Duke University, Johns Hopkins University (JHU) and University of Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) to ICI and pathogenic or likely pathogenic (P/LP) LRP1B alterations compared with LRP1B variants of unknown significance (VUS). Secondary outcomes were the associations with progression-free survival (PFS) and overall survival (OS) by LRP1B status.Results
We identified 101 patients (44 Duke, 35 JHU, 22 UM) with LRP1B alterations who were treated with ICI. The most common tumor types by alteration (P/LP vs VUS%) were lung (36% vs 49%), prostate (9% vs 7%), sarcoma (5% vs 7%), melanoma (9% vs 0%) and breast cancer (3% vs 7%). The ORR for patients with LRP1B P/LP versus VUS alterations was 54% and 13%, respectively (OR 7.5, 95% CI 2.9 to 22.3, p=0.0009). P/LP LRP1B alterations were associated with longer PFS (HR 0.42, 95% CI 0.26 to 0.68, p=0.0003) and OS (HR 0.62, 95% CI 0.39 to 1.01, p=0.053). These results remained consistent when excluding patients harboring microsatellite instability (MSI) and controlling for tumor mutational burden (TMB).Conclusions
This multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUS LRP1B alterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted.