Background: Full dose cabozantinib for metastatic renal cell carcinoma (mRCC) is 60 mg, but adverse events (AEs) may require dose reductions. Limited data exist comparing efficacy among cabozantinib doses. We compared AEs and clinical outcomes in mRCC patients treated with full vs. reduced starting cabozantinib dose. Methods: We performed a retrospective analysis of 87 mRCC patients treated with cabozantinib at Winship Cancer Institute from 2016 to 2019. Overall survival (OS), progression-free survival (PFS), and objective response (OR) rate measured clinical outcomes. AEs were collected from clinic notes and the most common were hypertension, mucositis/hand-foot skin reaction (HFSR), or gastrointestinal toxicity. Univariate analysis (UVA) between starting doses and AEs with clinical outcomes was performed using logistic regression model. Multivariable analysis was also performed using Cox proportional hazard model. Results: Most patients were men (71%) with clear-cell RCC (72%). The majority were IMDC intermediate (58%) or poor (35%) risk. One third received first-line cabozantinib and 64% had ≥3 baseline metastatic sites. Most patients (68%) required dose reduction from 60 mg or started at reduced dose without escalation. Reduced dose patients were more likely to have ≥3 distant metastatic sites (70% vs. 58%) and ≥2 prior lines of systemic therapy (50% vs. 40%) compared to full dose patients. UVA revealed a trend towards shorter OS (HR: 1.78, P = .095), PFS (HR: 1.50, P = .107), and lower chance of OR (HR:0.42, P = .149) among reduced dose patients. This trend did not hold in Multivariable analysis (OS HR: 1.20, P = .636; PFS HR: 1.23, P = .4662). Mucositis/HFSR and hypertension were significantly associated with improved outcomes in UVA. Conclusions: Although we found a trend favoring full dose cabozantinib, this is likely due to worse baseline disease characteristics among patients starting on a reduced dose. Hypertension and mucositis/HFSR may be associated with improved outcomes. Larger studies are warranted to validate these findings.

The role of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma is a subject of debate. We report a durable complete response in a 62-year-old man Jehovah’s Witness with metastatic clear cell renal cell carcinoma who received two cycles of nivolumab/ipilimumab followed by radical nephrectomy and metastasectomy of known pulmonary disease site, both without a clinical need for perioperative blood transfusions. The patient continues to be without evidence of disease and without additional need for systemic therapy over a year after his radical nephrectomy. The case highlights that cytoreductive nephrectomy continues to play a role in the era of immune checkpoint inhibitors.

Chemoresistance is a major obstacle in the clinical management of metastatic, castration-resistant prostate cancer (PCa). It is imperative to develop novel strategies to overcome chemoresistance and improve clinical outcomes in patients who have failed chemotherapy. Using a two-tier phenotypic screening platform, we identified bromocriptine mesylate as a potent and selective inhibitor of chemoresistant PCa cells. Bromocriptine effectively induced cell cycle arrest and activated apoptosis in chemoresistant PCa cells but not in chemoresponsive PCa cells. RNA-seq analyses revealed that bromocriptine affected a subset of genes implicated in the regulation of the cell cycle, DNA repair, and cell death. Interestingly, approximately one-third (50/157) of the differentially expressed genes affected by bromocriptine overlapped with known p53-p21- retinoblastoma protein (RB) target genes. At the protein level, bromocriptine increased the expression of dopamine D2 receptor (DRD2) and affected several classical and non-classical dopamine receptor signal pathways in chemoresistant PCa cells, including adenosine monophosphate-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa B (NF-κB), enhancer of zeste homolog 2 (EZH2), and survivin. As a monotherapy, bromocriptine treatment at 15 mg/kg, three times per week, via the intraperitoneal route significantly inhibited the skeletal growth of chemoresistant C4-2B-TaxR xenografts in athymic nude mice. In summary, these results provided the first preclinical evidence that bromocriptine is a selective and effective inhibitor of chemoresistant PCa. Due to its favorable clinical safety profiles, bromocriptine could be rapidly tested in PCa patients and repurposed as a novel subtype-specific treatment to overcome chemoresistance.

Background: Biomarkers have the potential to provide clinical guidance, but there is limited data for biomarkers in metastatic hormone sensitive prostate cancer (mHSPC). Methods: We performed a retrospective multicenter review from Winship Cancer Institute at Emory University and Georgia Cancer Center for Excellence at Grady Memorial Hospital (2014–2020) in the United States of America (USA). We collected demographics, disease characteristics, and laboratory data, including complete blood counts (CBC) at the start of upfront therapy. We evaluated overall survival (OS) and progression-free survival (PFS) associated with baseline lab values. Results: 165 patients were included with a median follow-up time of 33.5 months (mo). 105 (63.6%) had Gleason scores of 8-10 and 108 (65.9%) were classified as high-volume disease. 92 patients received upfront docetaxel (55.8%) and 73 received upfront abiraterone (44.2%). Univariate analyses (UVA) and multivariable analyses (MVA) identified worse clinical outcomes (CO) associated with elevated basophils and basophil-to-lymphocyte ratio (BLR). Based on MVA, elevated basophils (defined as ≥0.1, optimal cut) were associated with a hazard ratio (HR) of 3.51 (95% CI 1.65–7.43, P 0.001) for OS and HR of 1.88 (95% CI 1.05-3.38, P 0.034) for PFS. Our MVA also found that BLR ≥0.0142 was associated with HR 2.11 (95% CI 1.09–4.10, P 0.028) for OS; however, PFS was not statistically significant. Conclusion: We conclude that elevated baseline basophils and BLR are associated with worse clinical outcomes in mHSPC. Although results require further validation, BLR is a potential prognostic biomarker.

Introduction: There are three combination immune checkpoint inhibitor (ICI)–based regimens in the first-line setting for metastatic renal cell carcinoma (mRCC). Currently, there is limited real-world data for clinical outcomes and toxicity in mRCC patients treated with first-line ICI-based regimens. Methods: We performed a retrospective review of 49 mRCC patients treated with ICI-based combination regimens in the standard of care setting at the Winship Cancer Institute of Emory University from 2015–2020. We collected baseline data from the electronic medical record including demographic information and disease characteristics. Immune-related adverse events (irAEs) were collected from clinic notes and laboratory values. The primary clinical outcomes measured were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results: The median age was 65 years, and most patients (80%) were males. The majority were White (86%) and had clear cell RCC (83%). Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 (43%) or 1 (45%). Approximately one-half (49%) had at least three sites of distant metastatic disease. Most patients (88%) received nivolumab and ipilimumab. More than one-half (53%) of patients experienced an irAE, with 13 (27%) patients having treatment delayed and 18% discontinuing treatment for toxicity. The median OS was not reached, and the median PFS was 8.0 months per a Kaplan-Meier estimation. More than half of patients (53%) had a PFS > 6 months, and 22% had PFS > 1 year. The ORR was 33% for the entire cohort, and 7% of patients had a complete response. Conclusion: We presented real-world efficacy and toxicity data for front-line ICI combination treatment regimens. The ORR and median PFS were lower in our cohort of patients compared to the available data in the clinical trial setting. This was likely because of more advanced disease in this study. Future studies should provide additional data that will allow comparisons between different ICI combination regimens for untreated mRCC.

Although docetaxel significantly improves survival in a variety of malignancies, its clinical utility is severely restricted by acquired chemoresistance and disease relapse. To uncover the mechanisms underlying these all too common occurrences, an abundance of research has focused on mutations and gene expression patterns; however, these findings are yet to translate into improved outcomes for patients being administered this drug. These analyses have overlooked a promising lead in the quest to discern key mediators of resistance and relapse following docetaxel therapy: polyploidization. This process is manifested following docetaxel-mediated mitotic arrest by the appearance of giant, multinucleated cells, which slipped from mitosis without undergoing cytokinesis. Polyploid cells generally possess supernumerary centrosomes, are chromosomally instable, and resist chemotherapy. We thus suspect that chemoresistance and relapse following treatment with docetaxel might be combated by co-administration of centrosome declustering drugs, which could selectively destroy polyploid cells given that normal cells do not possess amplified centrosomes, an intriguing paradigm that warrants further investigation.

A major challenge to the treatment of advanced prostate cancer (PCa) is the development of resistance to androgen-deprivation therapy (ADT) and chemotherapy. It is imperative to discover effective therapies to overcome drug resistance and improve clinical outcomes. We have developed a novel class of silicon-containing compounds and evaluated the anticancer activities and mechanism of action using cellular and animal models of drug-resistant PCa. Five organosilicon compounds were evaluated for their anticancer activities in the NCI-60 panel and established drug-resistant PCa cell lines. GH1504 exhibited potent in vitro cytotoxicity in a broad spectrum of human cancer cells, including PCa cells refractory to ADT and chemotherapy. Molecular studies identified several potential targets of GH1504, most notably androgen receptor (AR), AR variant 7 (AR-v7) and survivin. Mechanistically, GH1504 may promote the protein turnover of AR, AR-v7 and survivin, thereby inducing apoptosis in ADT-resistant and chemoresistant PCa cells. Animal studies demonstrated that GH1504 effectively inhibited the in vivo growth of ADT-resistant CWR22Rv1 and chemoresistant C4-2B-TaxR xenografts in subcutaneous and intraosseous models. These preclinical results indicated that GH1504 is a promising lead that can be further developed as a novel therapy for drug-resistant PCa.

Reliable and routine isolation of circulating tumor cells (CTCs) from peripheral blood would allow effective monitoring of the disease and guide the development of personalized treatments. Negative enrichment of CTCs by depleting normal blood cells ensures against a biased selection of a subpopulation and allows the assay to be applied on different tumor types. Here, we report an additively manufactured microfluidic device that can negatively enrich viable CTCs from clinically-relevant volumes of unmanipulated whole blood samples. Our device depletes nucleated blood cells based on their surface antigens and the smaller anucleated cells based on their size. Enriched CTCs are made available off the device in suspension making our technique compatible with standard immunocytochemical, molecular and functional assays. Our device could achieve a ~ 2.34-log depletion by capturing > 99.5% of white blood cells from 10 mL of whole blood while recovering > 90% of spiked tumor cells. Furthermore, we demonstrated the capability of the device to isolate CTCs from blood samples collected from patients (n = 15) with prostate and pancreatic cancers in a pilot study. A universal CTC assay that can differentiate tumor cells from normal blood cells with the specificity of clinically established membrane antigens yet require no label has the potential to enable routine blood-based tumor biopsies at the point-of-care.

Background: Dried flower bud of Syzygium aromaticum (clove) is rich in eugenol, an antioxidant and antiinflammatory compound that can protect liver against injury. Clove, besides eugenol, also contains other pharmacologically active phytochemicals such as β-sitosterol and ascorbic acid. This study reports the effect of eugenol-rich fraction (ERF) of clove on liver cirrhosis induced by thioacetamide. Methods: Cirrhosis of the liver, which predisposes to hepatocellular carcinoma, was induced by administering thioacetamide (0.03%) in drinking water for 16 weeks. Cirrhotic animals were divided into two groups; the treated group was administered ERF for 9 weeks, one week after discontinuation of thioacetamide, while the other group received normal saline for a similar duration of time. Results: The treatment with ERF, as determined by histopathology and through a battery of biochemical markers of hepatic injury, oxidative stress and drug metabolizing enzymes, significantly ameliorated the signs of liver cirrhosis. It lowered the elevated levels of alkaline phosphatase, γ-glutamyl transferase and other biochemical changes in liver cirrhosis. Histopathology of the liver corroborated the effect of ERF with biochemical findings. ERF treatment further inhibited cell proliferation, as demonstrated by reduced [(3)H]-thymidine uptake. Conclusions: Data provide evidence supporting the protective action of ERF on liver cirrhosis. The study assumes significance because cirrhosis predisposes the liver to cancer, which is characterized by abnormal cell proliferation. ERF in this study is reported to inhibit hepatic cell proliferation and at the same time decrease oxidative stress, which might be the mechanism of protection against liver cirrhosis.

Background Sipuleucel-T (sip-T) is a Food and Drug Administration (FDA)-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). We hypothesized that combining sip-T with interleukin (IL)-7, a homeostatic cytokine that enhances both B and T cell development and proliferation, would augment and prolong antigen-specific immune responses against both PA2024 (the immunogen for sip-T) and prostatic acid phosphatase (PAP). Methods Fifty-four patients with mCRPC treated with sip-T were subsequently enrolled and randomized 1:1 into observation (n=26) or IL-7 (n=28) arms of a phase II clinical trial (NCT01881867). Recombinant human (rh) IL-7 (CYT107) was given weekly×4. Immune responses were evaluated using flow cytometry, mass cytometry (CyTOF), interferon (IFN)-γELISpot, 3 H-thymidine incorporation, and ELISA. Results Treatment with rhIL-7 was well tolerated. For the rhIL-7-treated, but not observation group, statistically significant lymphocyte subset expansion was found, with 2.3-2.6-fold increases in CD4+T, CD8+T, and CD56 bright NK cells at week 6 compared with baseline. No significant differences in PA2024 or PAP-specific T cell responses measured by IFN-γELISpot assay were found between rhIL-7 and observation groups. However, antigen-specific T cell proliferative responses and humoral IgG and IgG/IgM responses significantly increased over time in the rhIL-7-treated group only. CyTOF analyses revealed pleiotropic effects of rhIL-7 on lymphocyte subsets, including increases in CD137 and intracellular IL-2 and IFN-γexpression. While not powered to detect clinical outcomes, we found that 31% of patients in the rhIL-7 group had prostate specific antigen (PSA) doubling times of >6 months, compared with 14% in the observation group. Conclusions Treatment with rhIL-7 led to a significant expansion of CD4+ and CD8+ T cells, and CD56 bright natural killer (NK) cells compared with observation after treatment with sip-T. The rhIL-7 treatment also led to improved antigen-specific humoral and T cell proliferative responses over time as well as to increased expression of activation markers and beneficial cytokines. This is the first study to evaluate the use of rhIL-7 after sip-T in patients with mCRPC and demonstrates encouraging results for combination approaches to augment beneficial immune responses.