Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (17 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2022)

Prostate cancer remains the second leading cause of cancer death among men over 50 years old in the United States. Docetaxel is a taxane drug currently being used as a chemotherapy for advanced prostate cancer. However, prostate cancer patients often develop resistance to chemotherapy drugs. Therefore, we are interested in investigating new pathways that have the potential to overcome this resistance. From preliminary, independent analyses of ours and others, two new pathways have been shown to be important in advanced, therapy-resistant prostate cancer: ROR1 and CLIC1. ROR1 is the Receptor tyrosine kinase-like orphan receptor 1, an onco-embryonic antigen, which binds the WNT5A ligand and mediates non-canonical WNT signaling. The Chloride intracellular channel protein 1 (CLIC1) is known to be an important biomarker in several cancer types including prostate cancer. We sought to investigate the potential synergy of inhibitory therapies targeting ROR1 and CLIC1 with docetaxel. We hypothesized ROR1 and CLIC1 pathways as potential targets for therapies that can work either alone or in synergy with Docetaxel to inhibit prostate cancer progression. In this study, we sought to investigate the effect on cell proliferation and cell cycle of Docetaxel treatment and the inhibition of ROR1 and CLIC1 pathways. Through the optimization of cell-based assays using the Incucyte live cell microscope imaging technology, Docetaxel’s inhibitory effects on cell proliferation via G2 arrest was confirmed. Strikingly, our results revealed that without ROR1 expression, Docetaxel treatment leads to increased inhibition of cell proliferation, which we predict could lead to better outcomes in the clinic.

    • Thesis
    • Peer Reviewed
    UC San Diego Electronic Theses and Dissertations (2022)

    ABSTRACT OF THE THESIS

    Antitumor Activity of Chimeric Antigen T-cells Developed from Anti-ROR1 Monoclonal Antibody in Prostate Cancer Models

    by

    Jamillah H Murtadha

    Master of Science in Biological SciencesUniversity of California San Diego, 2022 Dr. Christina Jamieson, Chair Professor Maho Niwa, Co-Chair

    Prostate Cancer (PCa) is the second leading cause of cancer death in men, and there is no cure. The current treatments, such as Androgen Deprivation Therapy (ADT), cause adverse effects. ADT can be initially effective. However, PCa in most patients on ADT is eventually determined to be castration-resistant. Therefore, new therapies and treatments are needed. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is involved in embryogenesis. However, some findings correlate ROR1 with many cancers, including bone metastatic castrate-resistant PCa (CRPC) (Zhao et al., 2021)). Rather than using an anti-androgen drug to target CRPC, the drug therapy of interest is a biologic generated from chimeric antigen receptor (CAR) T-cells which targets the extracellular domain of ROR1 that has been derived from the monoclonal antibody, Cirmtuzumab. This study aims to determine the effects of anti-ROR1 CAR-T cells derived from Cirmtuzumab on prostate cancer tumors developed from PC3, a common prostate cancer cell line. For 145 days, we monitored the tumors of mice inoculated with anti-ROR1 CAR T-cells with an in-vivo bioluminescence imaging system assay, IVIS. By day 29, we observed 4 out of 9 mice had complete tumor regression. In conclusion, CAR T-cell treated mice with complete tumor regression had a longer survival rate of 145 days vs. 42 days for the control group animals. In conclusion, this pre-clinical study showed the efficacy of the Cirmtuzumab Anti-ROR1 CART against a human neuroendocrine prostate cancer tumor xenograft model in mice and supported additional studies on the path leading to human clinical trials.

      Cover page: Antitumor Activity of Chimeric Antigen T-cells Developed from anti-ROR1 Monoclonal Antibody in Prostate Cancer Models
      • Thesis
      • Peer Reviewed
      UC San Diego Electronic Theses and Dissertations (2017)

      One in six men will be diagnosed with prostate cancer (PCa), making it one of the leading health problems affecting men in today’s society. Patients diagnosed during the earlier stages are surviving longer due to improved therapies and the prevalence of prostate-specific antigen (PSA) testing. However, over 80% of advanced PCa patients develop bone metastatic prostate cancer for which there is no cure (Khan and Partin 2003). Cell lines, widely used for the development of new drug treatments and therapies, fail to accurately represent the heterogeneity of prostate cancer. Thus, it is important to establish new patient-derived cell culture models for bone metastatic prostate cancer which could better recapitulate the physiological processes that occur in vivo. Through the incorporation of previously established methods into our own culturing methods, we optimized three-dimensional cell culture conditions which keep our patient-derived xenograft (PDX) and primary patient tumor cells viable in vitro for a month and a half without passaging. Furthermore, preliminary experiments showed that our three-dimensional cultures consist of heterogeneous cell populations that exhibit different responses to the androgen hormone, dihydrotestosterone (DHT), and the anti-androgen drug, Enzalutamide. In future experiments, we hope to further optimize our culturing conditions to improve the robustness and reproducibility of our three-dimensional cell cultures for patient-derived xenograft and primary prostate cancer tumor cells.

        Cover page: Three-Dimensional Cell Culture Models of Bone Metastatic Prostate Cancer
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2021)
        Ewing sarcoma (ES) is the second most common pediatric bone cancer. Despite recent advances in the treatment, patients with metastatic tumors have dismal prognosis and hence novel therapies are urgently needed to combat this cancer. A recent study has shown that phosphoinositide-3 kinase (PI3K) inhibitors can synergistically increase sensitivity to bromodomain and extraterminal domain inhibitors in ES cells and therefore combined inhibition of PI3K and bromodomain and extraterminal domain bromodomain proteins might provide benefit in this cancer. Herein, we have investigated the efficacy of dual PI3K/BRD4 inhibitors, SF2523 and SF1126, for their antitumor activity in ES cell lines. The effect of SF1126 and SF2523 on cell viability and PI3K signaling was assessed on a panel of human ES cell lines. To evaluate the antitumor activity of SF1126, A673 cells were injected intrafemorally into RAG-2-/- mice and treated with 50 mg/kg SF1126 6 days per week, for 30 days. Both SF1126 and SF2523 decreased cell survival and inhibited phosphorylation of AKT in human ES cell lines. In vivo, SF1126 showed a significant reduction in tumor volume. These results suggest that dual PI3K/BRD4 inhibitor, SF1126, has antitumor activity in ES models.
          Cover page: Augmented Antitumor Activity for Novel Dual PI3K/BDR4 Inhibitors, SF2523 and SF1126 in Ewing Sarcoma
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2024)
          BACKGROUND: Non-canonical WNT family (WNT5A pathway) signaling via WNT5A through ROR1 and its partner, ROR2, or Frizzled2 (FZD2) is linked to processes driving tumorigenesis and therapy resistance. We utilized a large dataset of urothelial carcinoma (UC) tumors to characterize non-canonical WNT signaling through WNT5A, ROR1, ROR2, or FZD2 expression. METHODS: NextGen Sequencing of DNA (592 genes or WES)/RNA (WTS) was performed for 4125 UC tumors submitted to Caris Life Sciences. High and low expression of WNT5A, ROR1, ROR2, and FZD2 was defined as ≥ top and
            Cover page: Characterization and impact of non-canonical WNT signaling on outcomes of urothelial carcinoma.
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2018)
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2014)

              Background

              The presence of increased B-cell tumor infiltrating lymphocytes (TILs) was seen in mouse prostate cancer (PCa) but has not been fully documented in human PCa. We, therefore, investigated the density of infiltrating B cells within human PCa utilizing a quantitative computational method.

              Methods

              Archived radical prostatectomy specimens from 53 patients with known clinical outcome and D'Amico risk category were obtained and immunohistochemically (IHC) stained for the B cell marker, CD20. Slides were reviewed by a genitourinary pathologist who manually delineated the tumoral regions of PCa. Slides were digitally scanned and a computer algorithm quantified the area of CD20 stained B-cells as a measure of B cell density within the outlined regions of prostate cancer (intra-tumoral region), versus extra-tumoral prostate tissue. Correlations were analyzed between B-cell density and demographic and clinical variables, including D'Amico risk groups and disease recurrence.

              Results

              For the entire cohort, the mean intra-tumoral B cell density was higher (3.22 SE = 0.29) than in the extra-tumoral region of each prostatectomy section (2.24, SE = 0.19) (paired t test; P < 0.001). When analyzed according to D'Amico risk group, the intra-tumoral B cell infiltration in low risk (0.0377 vs. 0.0246; p = 0.151) and intermediate risk (0.0260 vs. 0.0214; p = 0.579) patient prostatectomy specimens did not show significantly more B-cells within the PCa tumor. However, patient specimens from the high-risk group (0.0301 vs. 0.0197; p < 0.001) and from those who eventually had PCa recurrence or progression (0.0343 vs. 0.0246; p = 0.019) did show significantly more intra-tumoral CD20+ B-cell staining. Extent of B-cell infiltration in the prostatectomy specimens did not correlate with any other clinical parameters.

              Conclusions

              Our study shows that higher B-cell infiltration was present within the intra-tumoral PCa regions compared to the extra-tumoral benign prostate tissue regions in prostatectomy sections. For this study we developed a new method to measure B-cells using computer-assisted digitized image analysis. Accurate, consistent quantitation of B-cells in prostatectomy specimens is essential for future clinical trials evaluating the effect of B cell ablating antibodies. The interaction of B-cells and PCa may serve as the basis for new therapeutic targets.
                Cover page: Tumor infiltrating B-cells are increased in prostate cancer tissue
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2016)

                Objective

                Bone metastasis occurs in up to 90% of men with advanced prostate cancer and leads to fractures, severe pain and therapy-resistance. Bone metastases induce a spectrum of types of bone lesions which can respond differently to therapy even within individual prostate cancer patients. Thus, the special environment of the bone makes the disease more complicated and incurable. A model in which bone lesions are reproducibly induced that mirrors the complexity seen in patients would be invaluable for pre-clinical testing of novel treatments. The microstructural changes in the femurs of mice implanted with PCSD1, a new patient-derived xenograft from a surgical prostate cancer bone metastasis specimen, were determined.

                Methods

                Quantitative micro-computed tomography (micro-CT) and histological analyses were performed to evaluate the effects of direct injection of PCSD1 cells or media alone (Control) into the right femurs of Rag2-/-γc-/- male mice.

                Results

                Bone lesions formed only in femurs of mice injected with PCSD1 cells. Bone volume (BV) was significantly decreased at the proximal and distal ends of the femurs (p < 0.01) whereas BV (p < 0.05) and bone shaft diameter (p < 0.01) were significantly increased along the femur shaft.

                Conclusion

                PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur, and, in contrast, induced aberrant bone formation leading to osteoblastic lesions along the femur shaft. Therefore, the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone lesion. Our approach can be used to determine if different bone regions support more therapy resistant tumor growth, thus, requiring novel treatments.
                  Cover page: Specific bone region localization of osteolytic versus osteoblastic lesions in a patient-derived xenograft model of bone metastatic prostate cancer
                  • Article
                  • Peer Reviewed
                  UC Davis Previously Published Works (2023)
                  Given that radium-223 is a radiopharmaceutical that induces DNA damage, and olaparib is a PARP inhibitor that interferes with DNA repair mechanisms, we hypothesized their synergy in metastatic castration-resistant prostate cancer (mCRPC). We sought to demonstrate the safety and efficacy of olaparib + radium-223. We conducted a multicenter phase I 3+3 dose escalation study of olaparib with fixed dose radium-223 in patients with mCRPC with bone metastases. The primary objective was to establish the RP2D of olaparib, with secondary objectives of safety, PSA response, alkaline phosphatase response, radiographic progression-free survival (rPFS), overall survival, and efficacy by homologous recombination repair (HRR) gene status. Twelve patients were enrolled; all patients received a prior androgen receptor signaling inhibitor (ARSI; 100%) and 3 patients (25%) prior docetaxel. Dose-limiting toxicities (DLT) included cytopenias, fatigue, and nausea. No DLTs were seen in the observation period however delayed toxicities guided the RP2D. The RP2D of olaparib was 200 mg orally twice daily with radium-223. The most common treatment-related adverse events were fatigue (92%) and anemia (58%). The rPFS at 6 months was 58% (95% confidence interval, 27%-80%). Nine patients were evaluable for HRR gene status; 1 had a BRCA2 alteration (rPFS 11.8 months) and 1 had a CDK12 alteration (rPFS 3.1 months). Olaparib can be safely combined with radium-223 at the RP2D 200 mg orally twice daily with fixed dose radium-223. Early clinical benefit was observed and will be investigated in a phase II study.
                    Cover page: A Phase I Study of Combination Olaparib and Radium-223 in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Bone Metastases (COMRADE).
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2020)

                    Background

                    Immunotherapeutic regulation of the tumor microenvironment in prostate cancer patients is not understood. Most antibody immunotherapies have not succeeded in prostate cancer. We showed previously that high-risk PCa patients have a higher density of tumor infiltrating B-cells in prostatectomy specimens. In mouse models, anti-CD20 antibody ablation of B-cells delayed PCa regrowth post-treatment. We sought to determine whether neoadjuvant anti-CD20 immunotherapy with rituximab could reduce CD20+ B cell infiltration of prostate tumors in patients.

                    Methods

                    An open label, single arm clinical trial enrolled eight high-risk PCa patients to receive one cycle of neoadjuvant rituximab prior to prostatectomy. Eleven clinical specimens with similar characteristics were selected as controls. Treated and control samples were concurrently stained for CD20 and digitally scanned in a blinded fashion. A new method of digital image quantification of lymphocytes was applied to prostatectomy sections of treated and control cases. CD20 density was quantified by a deconvolution algorithm in pathologist-marked tumor and adjacent regions. Statistical significance was assessed by one sided Welch's t-test, at 0.05 level using a gatekeeper strategy. Secondary outcomes included CD3+ T-cell and PD-L1 densities.

                    Results

                    Mean CD20 density in the tumor regions of the treated group was significantly lower than the control group (p = 0.02). Mean CD3 density in the tumors was significantly decreased in the treated group (p = 0.01). CD20, CD3 and PD-L1 staining primarily occurred in tertiary lymphoid structures (TLS). Neoadjuvant rituximab was well-tolerated and decreased B-cell and T-cell density within high-risk PCa tumors compared to controls.

                    Conclusions

                    This is the first study to treat patients prior to surgical prostate removal with an immunotherapy that targets B-cells. Rituximab treatment reduced tumor infiltrating B and T-cell density especially in TLSs, thus, demonstrating inter-dependence between B- and T-cells in prostate cancer and that Rituximab can modify the immune environment in prostate tumors. Future studies will determine who may benefit from using rituximab to improve their immune response against prostate cancer. Trial registration NCT01804712, March 5th, 2013 https://clinicaltrials.gov/ct2/show/NCT01804712?cond=NCT01804712&draw=2&rank=1.
                      Cover page: Neoadjuvant rituximab modulates the tumor immune environment in patients with high risk prostate cancer.
                      Top