Intermittent Androgen Deprivation for Biochemically Recurrent Prostate Cancer: First Do No Harm.

Intermittent androgen deprivation therapy in patients with prostate cancer and biochemical relapse does not prolong survival or improve quality of life.

Targeting ULK1 Decreases IFNγ-Mediated Resistance to Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICI) have transformed the treatment of melanoma. However, the majority of patients have primary or acquired resistance to ICIs, limiting durable responses and patient survival. IFNγ signaling and the expression of IFNγ-stimulated genes correlate with either response or resistance to ICIs, in a context-dependent manner. While IFNγ-inducible immunostimulatory genes are required for response to ICIs, chronic IFNγ signaling induces the expression of immunosuppressive genes, promoting resistance to these therapies. Here, we show that high levels of Unc-51 like kinase 1 (ULK1) correlate with poor survival in patients with melanoma and overexpression of ULK1 in melanoma cells enhances IFNγ-induced expression of immunosuppressive genes, with minimal effects on the expression of immunostimulatory genes. In contrast, genetic or pharmacologic inhibition of ULK1 reduces expression of IFNγ-induced immunosuppressive genes. ULK1 binds IRF1 in the nuclear compartment of melanoma cells, controlling its binding to the programmed death-ligand 1 promoter region. In addition, pharmacologic inhibition of ULK1 in combination with anti-programmed cell death protein 1 therapy further reduces melanoma tumor growth in vivo. Our data suggest that targeting ULK1 represses IFNγ-dependent immunosuppression. These findings support the combination of ULK1 drug-targeted inhibition with ICIs for the treatment of patients with melanoma to improve response rates and patient outcomes. IMPLICATIONS: This study identifies ULK1, activated downstream of IFNγ signaling, as a druggable target to overcome resistance mechanisms to ICI therapy in metastatic melanoma.

First-line Systemic Treatment of Recurrent Prostate Cancer After Primary or Salvage Local Therapy: A Systematic Review of the Literature.

CONTEXT: Several studies have investigated selection and sequencing of systemic agents to manage recurrent prostate cancer following local definitive treatment. OBJECTIVE: To define the incidence of recurrent prostate cancer in different countries, and systematically review management options and efficacy of first-line systemic therapies for patients with prostate cancer previously treated with definitive radical prostatectomy or radiation therapy. EVIDENCE ACQUISITION: We performed a systematic review of studies published from January 2010 to December 2021 in MEDLINE, EMBASE, or ClinicalTrials.gov according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Quality was assessed using the Grades of Recommendation, Assessment, Development and Evaluation methodology. The potential regional burdens of recurrent prostate cancer were estimated by analyzing various regional registry data. EVIDENCE SYNTHESIS: A total of 40 studies met the inclusion criteria and an additional landmark study published after the query was included in this review. Patients with metastatic recurrent disease derive benefit from the addition of androgen receptor signaling inhibitors to androgen deprivation therapy, while docetaxel should be reserved for patients with a high-volume metastatic burden by conventional imaging. Patients with biochemical-only recurrent disease benefit from continuous or intermittent androgen deprivation therapy if they possess high-risk features such as short prostate-specific antigen doubling time or high serum prostate-specific antigen. Current limitations to the published literature include no consideration of contemporary positron emission tomography imaging for evaluating metastatic recurrence or burden and few quality of life assessments. CONCLUSIONS: This systematic review summarizes the findings and recommendations for first-line systemic therapy for patients with recurrent prostate cancer following local therapy. PATIENT SUMMARY: We performed a systematic evaluation and summary of all studies published within the past decade on the topic of medications used to treat prostate cancer after it has recurred following radiation therapy or surgery. This review can be used to inform guidelines for prostate cancer management.

Antibody-drug conjugates and predictive biomarkers in advanced urothelial carcinoma.

The use of antibody-drug conjugates (ADCs) is expanding in several malignancies, including urothelial carcinoma where two of these medications have been approved for use and several others remain under study. ADCs act by binding to specific cell surface proteins, delivering anticancer agents directly to the target cells. Preclinical studies suggest that loss of these surface proteins alters sensitivity to therapy and expression of target proteins vary significantly based on the tumor subtype, prior therapies and other characteristics. However, use of biomarkers to predict treatment response have not been regularly included in clinical trials and clinician practice. In this review we summarize what is known about potential predictive biomarkers for ADCs in UC and discuss potential areas where use of biomarkers may improve patient care.

PARP Inhibition in Advanced Prostate Cancer.

ABSTRACT: In May 2020, the poly(ADP-ribose) polymerase (PARP) inhibitors rucaparib and olaparib were Food and Drug Administration approved for the management of metastatic castration-resistant prostate cancers. Rucaparib was approved for tumors that harbor alterations in BRCA1 and BRCA2 following progression on chemotherapy and androgen receptor-directed therapy, whereas olaparib was approved for tumors that harbor alterations in a broader range of DNA damage repair genes following progression on androgen receptor-directed therapy. Loss-of-function mutations in genes such as BRCA1 and BRCA2 increase reliance on PARP-mediated mechanisms of DNA repair, and inhibition of this pathway results in the accumulation of lethal levels of DNA damage. This dependence is advantageous in the management of prostate cancer, as mutations in DNA damage repair genes are frequent. This review summarizes the role of PARP in cell homeostasis, methods of targeting PARP in cancer cells, and current clinical trials in the management of advanced prostate cancer with PARP inhibitors.

Type I and II Interferons in the Anti-Tumor Immune Response.

The interferons (IFNs) are essential components of the immune response against infections and malignancies. IFNs are potent promoters of the anti-tumor response, but there is also evidence that feedback mechanisms regulated by IFNs negatively control immune responses to avoid hyper-activation and limit inflammation. This balance of responses plays an important role in cancer surveillance, immunoediting and response to anticancer therapeutic approaches. Here we review the roles of both type I and type II IFNs on the control of the immune response against malignancies in the context of effects on both malignant cells and cells of the immune system in the tumor microenvironment.

A multicenter characterization of hepatitis associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) predispose patients to immune-related adverse events (irAEs). Although hepatitis is a potentially lethal toxicity, the timing and outcomes have not been well described. In this retrospective study, patients from six international institutions were included if they were treated with ICIs and developed immune-related hepatitis. Patient and tumor characteristics, and hepatitis management and outcomes were evaluated. Of the 164 patients included, most were male (53.7%) with a median age of 63.0 years. Most patients had melanoma (83.5%) and stage IV disease (86.0%). Median follow-up was 585 days; median OS and PFS were not reached. The initial grade of hepatitis was most often grade 2 (30.5%) or 3 (45.7%) with a median time to onset of 61 days. Patients were most commonly asymptomatic (46.2%), but flu-like symptoms, including fatigue/anorexia (17.1%), nausea/emesis (14.0%), abdominal/back pain (11.6%), and arthralgias/myalgias (8.5%) occurred. Most patients received glucocorticoids (92.1%); the median time to improvement by one grade was 13.0 days, and the median time to complete resolution was 52.0 days. Second-line immunosuppression was required in 37 patients (22.6%), and steroid-dose re-escalation in 45 patients (27.4%). Five patients (3%) died of ICI-hepatitis or complications of hepatitis treatment. Ninety-one patients (58.6%) did not resume ICI; of 66 patients (40 grade 1/2, 26 grade 3/4) that were rechallenged, only 25.8% (n = 17) had recurrence. In this multi-institutional cohort, immune-related hepatitis was associated with excellent outcomes but frequently required therapy discontinuation, high-dose steroids, and second-line immunosuppression. Rechallenge was associated with a modest rate of hepatitis recurrence.

Epidemiology, mutational landscape and staging of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and rates of diagnosis have been fluctuating worldwide. In Western countries, HCC is driven primarily by the hepatitis C virus (HCV), alcohol use and non-alcoholic fatty liver disease (NAFLD). Hence, it is not surprising that the increased incidence of both HCV and NAFLD has been associated with a corresponding rise in rates of HCC. The introduction of antiviral medications could potentially change the landscape of HCC by reducing rates of HCV-associated HCC. In Eastern countries and Africa, HCC is driven primarily by hepatitis B virus (HBV), HCV, and to a lesser extent, aflatoxin exposure. The introduction of hepatitis B vaccines is expected to dramatically reduce hepatitis B induced liver damage and HCC. These varying etiologies of HCC result in different mutational landscapes, patient presentations and responses to treatment. This has made establishing a universal staging system difficult and several competing systems are available. Other than Sorafenib, there has also been a paucity of treatment options until the last two years, with immunotherapy and new-targeted tyrosine kinase inhibitors as potential treatment options. Management of HCC offers unique challenges during treatment, as there is often competing illness from underlying liver dysfunction and malignancy itself, both of which affects survival and treatment choice. The new era of treatment may offer additional options in this challenging field. In this review, we describe the underlying etiologies and associated mutational landscape, which drives the treatment options in this complex disease.

Clinical characterization of colitis arising from anti-PD-1 based therapy.

Colitis is a frequent, clinically-significant immune-related adverse event caused by anti-programmed death-1 (PD-1). The clinical features, timing, and management of colitis with anti-PD-1-based regimens are not well-characterized. Patients with advanced melanoma that received either anti-PD-1 monotherapy ("monotherapy") or combined with ipilimumab ("combination therapy") were screened from 8 academic medical centers, to identify those with clinically-relevant colitis (colitis requiring systemic steroids). Of 1261 patients who received anti-PD-1-based therapy, 109 experienced colitis. The incidence was 3.2% (30/937) and 24.4% (79/324) in the monotherapy and combination therapy cohorts, respectively. Patients with colitis from combination therapy had significantly earlier symptom onset (7.2 weeks vs 25.4 weeks, p < 0.0001), received higher steroid doses (median prednisone equivalent 1.5 mg/kg vs 1.0 mg/kg, p = 0.0015) and experienced longer steroid tapers (median 6.0 vs 4.0 weeks, p = 0.0065) compared to monotherapy. Infliximab use and steroid-dose escalation occurred more frequently in the combination therapy cohort compared to monotherapy. Nearly all patients had resolution of their symptoms although one patient died from complications. Anti-PD-1 associated colitis has a variable clinical presentation, and is more frequent and severe when associated with combination therapy. This variability in checkpoint-inhibitor associated colitis suggests that further optimization of treatment algorithms is needed.

Resistance mechanisms in melanoma to immuneoncologic therapy with checkpoint inhibitors.

Checkpoint inhibitors act by blocking physiologic mechanisms coopted by tumor cells to evade immune surveillance, restoring the immune system's ability to identify and kill malignant cells. These therapies have dramatically improved outcomes in multiple tumor types with durable responses in many patients, leading to FDA approval first in advanced melanoma, then in many other malignancies. However, as experience with checkpoint inhibitors has grown, populations of patients who are primary nonresponders or develop secondary resistance have been the majority of cases, even in melanoma. Mechanisms of resistance include those inherent to the tumor microenvironment, the tumor cells themselves, and the function of the patient's native immune cells. This review will discuss resistance to checkpoint inhibitors in melanoma as well as possible methods to restore sensitivity.

Emerging growth factor receptor antagonists for the treatment of advanced melanoma.

INTRODUCTION: Therapy for metastatic melanoma has undergone a rapid transformation over the past 5-10 years. Advances in immunotherapy with checkpoint inhibitors, including both anti-CTLA-4 and anti-PD-1/PD-L1, have led to durable responses in up to 50% of patients. As our understanding of the processes driving the transformation of melanocytes has improved, progress in targeted therapies has also continued. Areas covered: Angiogenesis and the tumor's dependence on an expanded vascular supply has been a target for novel therapies since the 1970's, as this tissue is derived from endothelial cells that are genetically stable in adults. A phase II trial studying combined therapy with bevacizumab (an inhibitor of angiogenesis) and ipilimumab found promising results. Other agents such as sorafenib have not been as successful, failing to extend progression free or overall survival in clinical trials. In this paper other targeted growth factor inhibitors will also be discussed. Expert opinion: Ultimately, melanoma may not be vulnerable solely to chemotherapy or targeted therapy, but may be efficaciously treated with immunotherapy due to its high mutational rate resulting in the expression of numerous neo-antigens. Therapies with combinations of agents including growth factor receptor and either other targeted therapies or immunotherapy may be a promising complimentary approach.

Targeting Fyn in Ras-transformed cells induces F-actin to promote adherens junction-mediated cell-cell adhesion.

Fyn, a member of the Src family kinases (SFK), is an oncogene in murine epidermis and is associated with cell-cell adhesion turnover and induction of cell migration. Additionally, Fyn upregulation has been reported in multiple tumor types, including cutaneous squamous cell carcinoma (cSCC). Introduction of active H-Ras(G12V) into the HaCaT human keratinocyte cell line resulted in upregulation of Fyn mRNA (200-fold) and protein, while expression of other SFKs remained unaltered. Transduction of active Ras or Fyn was sufficient to induce an epithelial-to-mesenchymal transition in HaCaT cells. Inhibition of Fyn activity, using siRNA or the clinical SFK inhibitor Dasatinib, increased cell-cell adhesion and rapidly (5-60 min) increased levels of cortical F-actin. Fyn inhibition with siRNA or Dasatinib also induced F-actin in MDA-MB-231 breast cancer cells, which have elevated Fyn. F-actin co-localized with adherens junction proteins, and Dasatinib-induced cell-cell adhesion could be blocked by Cytochalasin D, indicating that F-actin polymerization was a key initiator of cell-cell adhesion through the adherens junction. Conversely, inhibiting cell-cell adhesion with low Ca(2+) media did not block Dasatinib-induced F-actin polymerization. Inhibition of the Rho effector kinase ROCK blocked Dasatinib-induced F-actin and cell-cell adhesion, implicating relief of Rho GTPase inhibition as a mechanism of Dasatinib-induced cell-cell adhesion. Finally, topical Dasatinib treatment significantly reduced total tumor burden in the SKH1 mouse model of UV-induced skin carcinogenesis. Together these results identify the promotion of actin-based cell-cell adhesion as a newly described mechanism of action for Dasatinib and suggest that Fyn inhibition may be an effective therapeutic approach in treating cSCC.

FYNagling divergent adhesive functions for Fyn in keratinocytes.

Fyn, a member of the Src family kinases (SFKs), has been shown to play important yet contradictory roles in keratinocyte (KC) adhesion. During KC differentiation, physiological activation of Fyn results in the formation of adherens junctions, recruiting junctional components and inducing signaling pathways that control the differentiation program. However, in KC transformation and oncogenesis, increased Fyn activity has been implicated in the dissolution of adhesion structures and an increased migratory phenotype. Fyn activity is also associated with both the formation and dissolution of focal adhesions, and to a lesser extent hemidesmosomes and desmosomes. This viewpoint article aims to reconcile these disparate bodies of literature regarding Fyn's role in cell-cell and cell-matrix adhesion by proposing several alternative, testable hypotheses that unify Fyn's fractured functions.

Loss of protein kinase C delta gene expression in human squamous cell carcinomas: a laser capture microdissection study.

Protein kinase C delta (PKC-delta) protein levels are frequently low in chemically and UV-induced mouse skin tumors as well as in human cutaneous squamous cell carcinomas (SCCs). Furthermore, overexpression of PKC-delta in human SCC lines and mouse epidermis is sufficient to induce apoptosis and suppress tumorigenicity, making PKC-delta a potential tumor suppressor gene for SCCs. Here we report that PKC-delta is lost in human SCCs at the transcriptional level. We used laser capture microdissection to isolate cells from three normal human epidermis and 14 human SCCs with low PKC-delta protein. Analysis by quantitative reverse transcription-PCR revealed that PKC-delta RNA was reduced an average of 90% in the SCCs tested, consistent with PKC-delta down-regulation at the protein level. Analysis of DNA from nine of the same tumors revealed that PKC-delta gene was deleted in only one tumor. In addition, Ras-transformed human keratinocytes, which have selective down-regulation of PKC-delta at both protein and mRNA levels, had significantly repressed human PKC-delta promoter activity. Together, these results indicate that PKC-delta gene expression is suppressed in human SCCs, probably via transcription repression. Our results have implications for the development of topical therapeutic strategies to trigger the re-expression of pro-apoptotic PKC-delta to induce apoptosis in SCCs.

Evidence from the UK Zoonoses Action Plan in favour of localised anomalies of Salmonella infection on United Kingdom pig farms.

Salmonella spp. are important food-borne pathogens. Abattoir studies demonstrated that almost a quarter of British finisher pigs might carry Salmonella, which led to the introduction by the British Pig Executive of their Zoonoses Action Plan (ZAP) to monitor the Salmonella status of United Kingdom pig farms by testing meat juice samples using an ELISA system. We used the K-function and approaches from the field of geostatistics to study routine data from ZAP. We demonstrated that there is statistical evidence that geographically localized anomalies of Salmonella infection were present in one of three regions studied. The physical mechanisms underlying this structure remain unclear: spatial structure might be present as a result of shared spatially structured (second-order) or non-spatially structured (first-order) risk factors, transmission processes, or a combination of both. We have demonstrated a way to use routinely collected surveillance data to enhance the knowledge of spatial disease epidemiology.