Targeting PIKfyve-driven lipid metabolism in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism. For example, PDAC uses, and is dependent on, high levels of autophagy and other lysosomal processes. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the difficulty in identifying and characterizing favourable targets for drug development.

Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies.

The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling.

PIKfyve, expressed by CD11c-positive cells, controls tumor immunity.

Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy.

Discovery of LLC0424 as a Potent and Selective NSD2 PROTAC Degrader.

Nuclear receptor-binding SET domain-containing 2 (NSD2), a methyltransferase that primarily installs the dimethyl mark on lysine 36 of histone 3 (H3K36me2), has been recognized as a promising therapeutic target against cancer. However, existing NSD2 inhibitors suffer from low activity or inferior selectivity, and none of them can simultaneously remove the methyltransferase activity and chromatin binding function of NSD2. Herein we report the discovery of a novel NSD2 degrader by leveraging the proteolysis-targeting chimera technology.

p300/CBP degradation is required to disable the active AR enhanceosome in prostate cancer.

Prostate cancer is an exemplar of an enhancer-binding transcription factor-driven disease. The androgen receptor (AR) enhanceosome complex comprised of chromatin and epigenetic coregulators assembles at enhancer elements to drive disease progression. The paralog lysine acetyltransferases p300 and CBP deposit histone marks that are associated with enhancer activation.

Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development.

Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer.

Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, an orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients.

PIKfyve controls dendritic cell function and tumor immunity.

The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB).

Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer.

Mammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients.

Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies.

The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC.

Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy.

Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition of the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis, upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8 T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, increased intratumoral functional CD8 T cells, and slowed tumor progression in multiple syngeneic mouse models.

Proxalutamide reduces SARS-CoV-2 infection and associated inflammatory response.

Early in the COVID-19 pandemic, data suggested that males had a higher risk of developing severe disease and that androgen deprivation therapy might be associated with protection. Combined with the fact that (), a host entry factor for the SARS-CoV-2 virus, was a well-known androgen-regulated gene, this led to an upsurge of research investigating androgen receptor (AR)-targeting drugs. Proxalutamide, an AR antagonist, was shown in initial clinical studies to benefit COVID-19 patients; however, further validation is needed as one study was retracted.

Is a Prognostic Biomarker That Correlates With Cell Malignancy and the Tumor Microenvironment in Bladder Cancer.

Prostate transmembrane protein androgen induced 1 () has been reported to promote cancer progression, but the potential role of in bladder cancer (BLCA) remains elusive. We assess the role of in BLCA, a publicly available database and study. was identified from 107 differentially expressed genes (DEGs) to have prognostic value.

Efficacy of Intra-Arterial Plus Intravesical Chemotherapy for High-Risk Non-Muscle-Invasive Bladder Cancer: A Pooled Analysis.

The treatment for high-risk non-muscle-invasive bladder cancer (NMIBC) remains highly debated for its high recurrence and progression risk. This work aimed to verify the efficacy and toxicity of intra-arterial chemotherapy (IAC) plus intravesical chemotherapy (IVC) in high-risk NMIBC. A comprehensive online literature search was conducted in three databases to select researches related to IAC + IVC for high-risk NMIBC.

Recurrence factors in patients with Keratinizing squamous metaplasia of the bladder after surgical management: a single-center retrospective study.

Background: Keratinizing squamous metaplasia (KSM) is a clinically heterogeneous disease that lacks research that provide definitive recurrent risk factors. Therefore, we identified the recurrence factors in patients with KSM of the bladder after transurethral resection (TUR). We also attempted to investigate the association between KSM and bladder cancer.

Smoking status and pathological response to neoadjuvant chemotherapy among patients with bladder cancer: a pooled analysis.

Background: Smoking status has been confirmed as an independent prognostic factor for bladder cancer. However, for patients who received neoadjuvant chemotherapy (NAC), the influence of smoking status on the pathological response and prognosis remains unclear. This pooled analysis aimed to investigate whether smoking status is an independent risk factor for pathological response, recurrence, and prognosis in patients with bladder cancer who undergo NAC.

Clinicopathologic Features and Survival Outcomes for Primary Renal Neuroendocrine Neoplasms.

Purpose: Primary renal neuroendocrine neoplasms (NENs) are exceedingly rare. We used the Surveillance, Epidemiology, and End Results (SEER) data to summarize clinicopathologic characteristics, treatment outcomes, and prognostic factors of primary renal NENs.

Methods: Data were identified from the SEER database.

Effect of neoadjuvant chemotherapy on locally advanced upper tract urothelial carcinoma: a pooled analysis.

Background: The outcome of neoadjuvant chemotherapy (NAC) has been established in bladder cancer but remains controversial in upper tract urothelial carcinoma (UTUC). In this work, we explored the therapeutic effect of NAC in patients with locally advanced UTUC.

Methods: We conducted a literature search on articles published from 1995 up to April 2020 in PubMed/Medline, the Cochrane Library, Embase, Google Scholar.

A preoperative nomogram predicting the pseudocapsule status in localized renal cell carcinoma.

Background: Tumor enucleation (TE) surgery for localized renal cell carcinoma (RCC) relies on a complete peritumoral pseudocapsule (PC). Study objective was to develop a preoperative model to predict PC status.

Methods: The prediction model was developed in a cohort that consisted of 170 patients with localized RCC, and data was gathered from 2010 to 2015.

A nomogram incorporating PD-L1, NLR, and clinicopathologic features to predict inguinal lymph node metastasis in penile squamous cell carcinoma.

Background: Accurate preoperative prediction of inguinal lymph node metastasis (LNM) aids in clinical decision making, especially for patients with penile cancer with clinically negative lymph nodes. We aim to develop a nomogram to predict the preoperative risk of LNM by incorporating clinicopathologic features and tumor biomarkers.

Methods: Eighty-four patients with penile cancer with clinically negative lymph nodes were enrolled.

Do cerebral and somatic tissue oxygen saturation measurements correlate with each other during surgery?

Intraoperative maintenance of optimal tissue oxygenation is critical; however, it is uncertain whether measurements of different tissue beds correlate with each other. Cerebral tissue oxygen saturation (SctO) measured on the forehead and somatic tissue oxygen saturation (SstO) measured on limbs, using a tissue near-infrared spectroscopy, were simultaneously recorded every 2 s in patients having spine surgery or robotic hysterectomy. Simple linear regression was used to determine the static correlation between SctO and SstO using the median values of each min for each patient.