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The mechanisms by which prostate cancer shifts from an indolent castration-sensitive phenotype to lethal castration-resistant prostate cancer (CRPC) are poorly understood. Identification of clinically relevant genetic alterations leading to CRPC may reveal potential vulnerabilities for cancer therapy. Here we find that CUB domain-containing protein 1 (CDCP1), a transmembrane protein that acts as a substrate for SRC family kinases (SFKs), is overexpressed in a subset of CRPC. Notably, CDCP1 cooperates with the loss of the tumor suppressor gene PTEN to promote the emergence of metastatic prostate cancer. Mechanistically, we find that androgens suppress CDCP1 expression and that androgen deprivation in combination with loss of PTEN promotes the upregulation of CDCP1 and the subsequent activation of the SRC/MAPK pathway. Moreover, we demonstrate that anti-CDCP1 immunoliposomes (anti-CDCP1 ILs) loaded with chemotherapy suppress prostate cancer growth when administered in combination with enzalutamide. Thus, our study identifies CDCP1 as a powerful driver of prostate cancer progression and uncovers different potential therapeutic strategies for the treatment of metastatic prostate tumors., Introduction Castration-resistant prostate cancer (CRPC) is the second leading cause of death among men in developed countries (1). Although second-generation androgen-deprivation therapies (ADTs) have been successfully used to treat CRPC, [...]

In spite of the recent approval of new promising targeted therapies, the clinical outcome of patients with acute myeloid leukemia (AML) remains suboptimal, prompting the search for additional and synergistic therapeutic rationales. It is increasingly evident that the bone marrow immune environment of AML patients is profoundly altered, contributing to the severity of the disease but also providing several windows of opportunity to prompt or rewire a proficient antitumor immune surveillance. In this Review, we present current evidence on immune defects in AML, discuss the challenges with selective targeting of AML cells, and summarize the clinical results and immunologic insights from studies that are testing the latest immunotherapy approaches to specifically target AML cells (antibodies, cellular therapies) or more broadly reactivate antileukemia immunity (vaccines, checkpoint blockade). Given the complex interactions between AML cells and the many components of their environment, it is reasonable to surmise that the future of immunotherapy in AML lies in the rational combination of complementary immunotherapeutic strategies with chemotherapeutics or other oncogenic pathway inhibitors. Identifying reliable biomarkers of response to improve patient selection and avoid toxicities will be critical in this process., Introduction Acute myeloid leukemia (AML) is a genetically, epigenetically, and clinically heterogeneous disease characterized by accumulation and expansion of immature myeloid cells in the bone marrow (BM) and peripheral blood [...]

EGFR-mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as [EGFR.sup.T790M] and [EGFR.sup.C7975]. It is generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, but contrary to this, we uncovered here that gefitinib and osimertinib increased STAT3 phosphorylation (p-STAT3) in [EGFR.sup.T790M] and [EGFR.sup.C7975] tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induced a p-STAT3-dependent strong reduction in the levels of the transcriptional repressor HES1. Importantly, we showed that tyrosine kinase inhibitor-resistant tumors, with [EGFR.sup.T790M] and [EGFR.sup.C7975] mutations, were highly responsive to the combined treatment of Notch inhibitors with gefitinib or osimertinib, respectively. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increased during relapse and correlated with shorter progression-free survival. Therefore, our results offer a proof of concept for an alternative treatment to chemotherapy in lung adenocarcinoma osimertinib- treated patients after disease progression., Introduction Lung cancer kills approximately 1 million people every year worldwide and is the leading cause of death by cancer in the world. Lung cancer consists of 2 main types: [...]

Background: Observational studies comparing uniportal and multiportal video-assisted thoracoscopic surgery (VATS) in the treatment of lung cancer have produced conflicting results. We present a Canadian study comparing clinical outcomes of uniportal and multiportal VATS in the treatment of lung cancer. Methods: A retrospective study evaluating patients who underwent multiportal (2012-2014) or uniportal (2014-2016) VATS lobectomies, segmentectomies and wedge resections for lung cancer. Clinical outcomes measured included patient demographics, tumour factors, operative factors, length of hospital stay, postoperative complications, analgesic use, pain scores and mortality. Descriptive statistics were used to compare the 2 groups. Results: Of 185 patients, 65 underwent uniportal and 63 underwent multiportal VATS resection. Patients were similar in terms of their baseline demographics, comorbidies and cancer characteristics. Median operative time was 184 and 185 minutes in the uniportal and multiportal groups, respectively. There were 5 conversions to thoracotomy in the uniportal group and 1 in the multiportal group. Similar lymph node retrieval (median 7 v. 5 nodes) and positive margin rates (6.2% v. 4.8%) were seen in the 2 groups. Median length of stay was 2 days (interquartile range [IQR] 1-3) and 3 days (IQR 2-4) in the uniportal and multiportal groups, respectively. Rates of postoperative complications were similar in the 2 groups (16.9% v. 19.0%, p = 0.76). Patient-controlled analgesia use and pain scores did not differ between the groups. Conclusion: Adoption of uniportal VATS appears to be feasible and safe, without compromising oncologic principles or increasing intraoperative resource utilization. Larger, prospective studies can help confirm these findings. Contexte: Les etudes observationnelles qui comparent les interventions chirurgicales par thoracoscopie video-assistee (VATS) uniportale et multiportale dans le traitement du cancer du poumon se contredisent. Notre etude compare les resultats cliniques des 2 types d'interventions en milieu canadien, pour les patients atteints d'un cancer du poumon. Methodes: Nous avons retrospectivement etudie le dossier de patients qui ont subi une lobectomie, une segmentectomie ou une resection cuneiforme peripherique par VATS multiportale (2012-2014) ou uniportale (2014-2016) pour cause de cancer du poumon. Les variables examinees etaient les caracteristiques personnelles des patients, les caracteristiques des tumeurs, les parametres et details de l'intervention, la duree d'hospitalisation, les complications postoperatoires, l'utilisation d'analgesiques, l'intensite de la douleur ressentie et la mortalite. Nous avons compare les 2 groupes a l'aide de statistiques descriptives. Resultats: Sur les 185 patients reperes, 65 avaient subi une VATS uniportale, et 63, une VATS multiportale. Les participants des 2 groupes se ressemblaient sur le plan de leur situation personnelle, de leurs comorbidites et des caracteristiques de leur cancer. La duree mediane de l'intervention etait de 184 minutes pour les operations uniportales et de 185 minutes pour les operations multiportales. Les chirurgiens sont passes a la thoracotomie lors de 5 interventions uniportales et d'une intervention multiportale. Le nombre median de noeuds lymphoides retires (7 c. 5) et le taux de marges positives (6,2% c. 4,8%) etaient comparables entre les 2 groupes. La duree mediane d'hospitalisation etait de 2 jours dans le groupe d'intervention uniportale et de 3 jours dans le groupe d'intervention multiportale (intervalle interquartile 1-3 et 2-4, respectivement). Le taux de complications postoperatoires etait semblable (16,9% c. 19,0%; p = 0,74), tout comme l'utilisation d'analgesiques controlee par le patient et l'intensite de la douleur ressentie. Conclusion: Il semble que l'adoption de la VATS uniportale soit realiste et sure, assurerait le respect des principes oncologiques et n'accroitrait pas l'utilisation de ressources en contexte operatoire. Il faudra cependant mener des etudes prospectives de plus grande envergure pour confirmer ces resultats., In the past decade, numerous meta-analyses have demonstrated that video-assisted thoracoscopic surgery (VATS) is associated with shorter hospital stays, reduced complication rates and improved long-term survival when compared with open [...]

More than half of patients diagnosed with cancer have comorbid conditions. Yet once cancer treatment begins, patients sense that they don't need to see their primary care physician, and that [...]

Natural killer (NK) cells are innate cytotoxic lymphocytes involved in the surveillance and elimination of cancer. As we have learned more and more about the mechanisms NK cells employ to recognize and eliminate tumor cells, and how, in turn, cancer evades NK cell responses, we have gained a clear appreciation that NK cells can be harnessed in cancer immunotherapy. Here, we review the evidence for NK cells' critical role in combating transformed and malignant cells, and how cancer immunotherapies potentiate NK cell responses for therapeutic purposes. We highlight cutting-edge immunotherapeutic strategies in preclinical and clinical development such as adoptive NK cell transfer, chimeric antigen receptor-expressing NK cells (CAR-NKs), bispecific and trispecific killer cell engagers (BiKEs and TriKEs), checkpoint blockade, and oncolytic virotherapy. Further, we describe the challenges that NK cells face (e.g., postsurgical dysfunction) that must be overcome by these therapeutic modalities to achieve cancer clearance., NK cells: sentinels against cancer The existence of immune cells that mediate cellular cytotoxicity without prior activation was determined by multiple groups who reported the spontaneous killing of tumor cells [...]

Gliomas account for approximately 80% of primary malignant tumors in the central nervous system. Despite aggressive therapy, the prognosis of patients remains extremely poor. Glioma stem cells (GSCs), considered a potential target of therapy for their crucial role in therapeutic resistance and tumor recurrence, are believed to be key factors in the disappointing outcome. Here, we took advantage of GSCs as the cell model to perform high-throughput drug screening, and the old antibiotic clofoctol was identified as the most effective compound, showing reduction of colony formation and induction of apoptosis of GSCs. Moreover, growth of tumors was obviously inhibited in vivo after clofoctol treatment especially in primary patient-derived xenografts and transgenic xenografts. The anticancer mechanisms demonstrated by analysis of related downstream genes and discovery of the targeted binding protein revealed that clofoctol exhibited the inhibition of GSCs by upregulation of Kruppel-like factor 13 (KLF13), a tumor suppressor gene, through clofoctol's targeted binding protein, Upstream of N-ras (UNR). Collectively, these data demonstrate that induction of KLF13 expression suppressed growth of gliomas and provide a potential therapy for gliomas targeting GSCs. Importantly, our results also identify the RNA-binding protein UNR as a drug target., Introduction Gliomas are the most common type of primary malignant tumor in the central nervous system. Among these, glioblastoma, or WHO grade IV glioma, accounts for 55% of all cases [...]

Epigenetic dysregulation is a common feature of most cancers, often occurring directly through alteration of epigenetic machinery. Over the last several years, a new generation of drugs directed at epigenetic modulators have entered clinical development, and results from these trials are now being disclosed. Unlike first-generation epigenetic therapies, these new agents are selective, and many are targeted to proteins which are mutated or translocated in cancer. This review will provide a summary of the epigenetic modulatory agents currently in clinical development and discuss the opportunities and challenges in their development. As these drugs advance in the clinic, drug discovery has continued with a focus on both novel and existing epigenetic targets. We will provide an overview of these efforts and the strategies being employed. Targeting epigenetic modifications is an effective cancer therapeutic approach and can be combined with other therapeutics for maximal effect., Author(s): Helai P. Mohammad [sup.1] , Olena Barbash [sup.1] , Caretha L. Creasy [sup.1] Author Affiliations: (1) Epigenetics Department, Oncology, GlaxoSmithKline, Collegeville, USA Main Epigenetic alterations are covalent modifications to [...]