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The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling 1 and is altered in over 20% of cancers 2 , 3 . Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR) + forkhead box A1 (FOXA1) + prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis -regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR , FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers. PROTAC degrader–induced SWI/SNF inactivation abolishes DNA accessibility at enhancer elements of oncogenes and also tempers supra-physiologic expression of driver transcription factors, resulting in potent inhibition of tumour growth in mouse models.

Cancer, the main cause of human deaths in the modern world is a group of diseases. Anticancer drug discovery is a challenge for scientists because of involvement of multiple survival pathways of cancer cells. An extensive study on the regulation of each step of these pathways may help find a potential cancer target. Up-regulated HIF-1 expression and altered metabolic pathways are two classical characteristics of cancer. Oxygen-dependent (through pVHL, PHDs, calcium-mediated) and independent (through growth factor signaling pathway, mdm2 pathway, HSP90) regulation of HIF-1α leads to angiogenesis, metastasis, and cell survival. The two subunits of HIF-1 regulates in the same fashion through different mechanisms. HIF-1α translation upregulates via mammalian target of rapamycin and mitogen-activated protein kinase signaling pathways, whereas HIF-1β through calmodulin kinase. Further, the stabilized interactions of these two subunits are important for proper functioning. Also, metabolic pathways crucial for the formation of building blocks (pentose phosphate pathway) and energy generation (glycolysis, TCA cycle and catabolism of glutamine) are altered in cancer cells to protect them from oxidative stress and to meet the reduced oxygen and nutrient supply. Up-regulated anaerobic metabolism occurs through enhanced expression of hexokinase, phosphofructokinase, triosephosphate isomerase, glucose 6-phosphate dehydrogenase and down-regulation of aerobic metabolism via pyruvate dehydrogenase kinase and lactate dehydrogenase which compensate energy requirements along with high glucose intake. Controlled expression of these two pathways through their common intermediate may serve as potent cancer target in future.

Both KRAS and EGFR are essential mediators of pancreatic cancer development and interact with Argonaute 2 (AGO2) to perturb its function. Here, in a mouse model of mutant KRAS-driven pancreatic cancer, loss of AGO2 allows precursor lesion (PanIN) formation yet prevents progression to pancreatic ductal adenocarcinoma (PDAC). Precursor lesions with AGO2 ablation undergo oncogene-induced senescence with altered microRNA expression and EGFR/RAS signaling, bypassed by loss of p53 . In mouse and human pancreatic tissues, PDAC progression is associated with increased plasma membrane localization of RAS/AGO2. Furthermore, phosphorylation of AGO2 Y393 disrupts both the wild-type and oncogenic KRAS-AGO2 interaction, albeit under different conditions. ARS-1620 (G12C-specific inhibitor) disrupts the KRAS G12C -AGO2 interaction, suggesting that the interaction is targetable. Altogether, our study supports a biphasic model of pancreatic cancer development: an AGO2 -independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2 -dependent phase wherein the mutant KRAS-AGO2 interaction is critical for PDAC progression. Argonaute 2 (AGO2) binds RAS and is required for cellular transformation. Here, the authors establish a KRAS-driven mouse model of pancreatic cancer with conditional loss of AGO2 and show that the early phase of neoplastic lesion initiation is dependent on EGFR/RAS but not AGO2, while AGO2 is required for pancreatic ductal adenocarcinoma progression and metastasis.

Multiple myeloma is the second most common hematological malignancy. Despite significant advances in treatment, relapse is common and carries a poor prognosis. Thus, it is critical to elucidate the genetic factors contributing to disease progression and drug resistance. Here, we carry out integrative clinical sequencing of 511 relapsed, refractory multiple myeloma (RRMM) patients to define the disease’s molecular alterations landscape. The NF-κB and RAS/MAPK pathways are more commonly altered than previously reported, with a prevalence of 45–65% each. In the RAS/MAPK pathway, there is a long tail of variants associated with the RASopathies. By comparing our RRMM cases with untreated patients, we identify a diverse set of alterations conferring resistance to three main classes of targeted therapy in 22% of our cohort. Activating mutations in IL6ST are also enriched in RRMM. Taken together, our study serves as a resource for future investigations of RRMM biology and potentially informs clinical management. The genetic factors involved in disease progression and drug resistance in multiple myeloma (MM) are varied and complex. Here, genomic and transcriptomic profiling of 511 relapsed and refractory MM patients reveals genetic alterations in several oncogenic pathways contributing to progression and resistance to MM therapies.

Microphthalmia-associated transcription factor (MiT) family aberration-associated renal cell carcinoma (MiTF-RCC) is a subtype of renal cell carcinoma harboring recurrent chromosomal rearrangements involving TFE3 or TFEB genes. MiTF-RCC is morphologically diverse, can histologically resemble common RCC subtypes like clear cell RCC and papillary RCC, and often poses a diagnostic challenge in genitourinary clinical and pathology practice. To characterize the MiTF-RCC at the molecular level and identify biomarker signatures associated with MiTF-RCC, we analyzed RNAseq data from MiTF-RCC, other RCC subtypes and benign kidney. Upon identifying TRIM63 as a cancer-specific biomarker in MiTF-RCC, we evaluated its expression independently by RNA in situ hybridization (RNA-ISH) in whole tissue sections from 177 RCC cases. We specifically included 31 cytogenetically confirmed MiTF-RCC cases and 70 RCC cases suspicious for MiTF-RCC in terms of clinical and morphological features, to evaluate and compare TRIM63 RNA-ISH results with the results from TFE3/TFEB fluorescence in situ hybridization (FISH), which is the current clinical standard. We confirmed that TRIM63 mRNA was highly expressed in all classes of MiTF-RCC compared to other renal tumor categories, where it was mostly absent to low. While the TRIM63 RNA-ISH and TFE3/TFEB FISH results were largely concordant, importantly, TRIM63 RNA-ISH was strongly positive in TFE3 FISH false-negative cases with RBM10-TFE3 inversion. In conclusion, TRIM63 can serve as a diagnostic marker to distinguish MiTF-RCC from other renal tumor subtypes with overlapping morphology. We suggest a combination of TFE3/TFEB FISH and TRIM63 RNA-ISH assays to improve the accuracy and efficiency of MiTF-RCC diagnosis. Accurate diagnosis of MiTF-RCC and other RCC subtypes would enable effective targeted therapy and avoid poor therapeutic response due to tumor misclassification.

Background TMPRSS2-ERG gene rearrangement, the most common E26 transformation specific (ETS) gene fusion within prostate cancer, is known to contribute to the pathogenesis of this disease and carries diagnostic annotations for prostate cancer patients clinically. The ERG rearrangement status in prostatic adenocarcinoma currently cannot be reliably identified from histologic features on H&E-stained slides alone and hence requires ancillary studies such as immunohistochemistry (IHC), fluorescent in situ hybridization (FISH) or next generation sequencing (NGS) for identification. Methods Objective We accordingly sought to develop a deep learning-based algorithm to identify ERG rearrangement status in prostatic adenocarcinoma based on digitized slides of H&E morphology alone. Design Setting, and Participants: Whole slide images from 392 in-house and TCGA cases were employed and annotated using QuPath. Image patches of 224 × 224 pixel were exported at 10 ×, 20 ×, and 40 × for input into a deep learning model based on MobileNetV2 convolutional neural network architecture pre-trained on ImageNet. A separate model was trained for each magnification. Training and test datasets consisted of 261 cases and 131 cases, respectively. The output of the model included a prediction of ERG-positive (ERG rearranged) or ERG-negative (ERG not rearranged) status for each input patch. Outcome measurements and statistical analysis: Various accuracy measurements including area under the curve (AUC) of the receiver operating characteristic (ROC) curves were used to evaluate the deep learning model. Results and Limitations All models showed similar ROC curves with AUC results ranging between 0.82 and 0.85. The sensitivity and specificity of these models were 75.0% and 83.1% (20 × model), respectively. Conclusions A deep learning-based model can successfully predict ERG rearrangement status in the majority of prostatic adenocarcinomas utilizing only H&E-stained digital slides. Such an artificial intelligence-based model can eliminate the need for using extra tumor tissue to perform ancillary studies in order to assess for ERG gene rearrangement in prostatic adenocarcinoma.

Despite early diagnosis and established protocols, a subset of prostate cancer patients will eventually be categorized as castration-resistant prostate cancer. Recently, it has been reported that these multi-modal therapy cases may harbor a special subset of cancer cells termed as polypoidal giant cancer cells (PGCC). These cells are phenotypically described either as possessing highly irregular polylobated nuclei or multiple pleomorphic nuclei. To identify and characterize the distribution of these cells, we created a cohort of 5 randomly selected cases of multi-modal therapy failure prostate cancer (16 selected non-osseous and osseous tumor sites) enrolled in Michigan Legacy Tissue Program. In all cases, specific “regions of interest” or “hot spots” within tumor areas showing an increased proportion of these multi-nucleated/polylobated cells under light microscopy were labeled as PGCC-rich area. On microscopic evaluation, overall mean count of PGCC was 42.4 ± 3.91 with case 2 in the study cohort with the highest number of average PGCC count of 17 ± 4.04. Site wise analysis showed retroperitoneal lymph node as the tissue with highest number of average PGCC number/site (5.0 ± 0.32). On correlating the average number of PGCC recorded with the time elapsed from last dose of chemotherapy administered to autopsy, the spearman correlation value (R) was 0.67, but the result was not statistically significant (p = 0.22). A systematic assessment of PGCC in a large stratified cohort of prostate cancer patients integrated with various histopathological and clinical parameters along with discovery of specific biomarkers for PGCC are the future studies suggested.

Lysine-specific demethylase 1 (LSD1) is a histone demethylase that promotes stemness and cell survival in cancers such as prostate cancer. Most prostate malignancies are adenocarcinomas with luminal differentiation. However, some tumors undergo cellular reprogramming to a more lethal subset termed neuroendocrine prostate cancer (NEPC) with neuronal differentiation. The frequency of NEPC is increasing since the widespread use of potent androgen receptor signaling inhibitors. Currently, there are no effective treatments for NEPC. We previously determined that LSD1 promotes survival of prostate adenocarcinoma tumors. However, the role of LSD1 in NEPC is unknown. Here, we determined that LSD1 is highly upregulated in NEPC versus adenocarcinoma patient tumors. LSD1 suppression with RNAi or allosteric LSD1 inhibitors — but not catalytic inhibitors — reduced NEPC cell survival. RNA-Seq analysis revealed that LSD1 represses pathways linked to luminal differentiation, and TP53 was the top reactivated pathway. We confirmed that LSD1 suppressed the TP53 pathway by reducing TP53 occupancy at target genes while LSD1’s catalytic function was dispensable for this effect. Mechanistically, LSD1 inhibition disrupted LSD1-HDAC interactions, increasing histone acetylation at TP53 targets. Finally, LSD1 inhibition suppressed NEPC tumor growth in vivo. These findings suggest that blocking LSD1’s noncatalytic function may be a promising treatment strategy for NEPC.

Neuroendocrine transdifferentiation of high-grade prostate cancer (PCA-NT) comprises a morphologic and immunophenotypic transition from conventional adenocarcinoma towards high-grade neuroendocrine/small cell carcinoma. This phenomenon is frequently observed post androgen deprivation and/or radiotherapy, but de novo instances are increasingly recognized. Herein, we report a series of de novo PCA-NT focusing on characteristic morphologic, immunophenotypic and clinical features. Treatment naïve PCA-NT were identified. IHC for PSA, NKX3.1, Chromogranin, Synaptophysin, Cyclin D1, RB and Ki67 were performed. Radiology, treatment and follow-up data were reviewed. Sixteen patients were included. Apart from focal areas of high-grade prostate cancer with acinar features (reminiscent of Grade Group 5 disease), extensive areas with sheets of cells with deep amphophilic/basophilic cytoplasm, enlarged, hyperchromatic nuclei with granular chromatin and inconspicuous to prominent nucleoli with high mitotic activity were identified. Immunohistochemistry showed patchy NKX3.1, patchy PSA, variable Synaptophysin and Chromogranin; RB and CyclinD1 showed loss of expression. Ki67 showed high proliferative index, in most cases. Adverse radiologic findings and metastases were documented in most cases. Two patients died of disease. De novo PCA-NT exhibits high-grade nuclei, high mitotic activity, reduced PSA expression with high Ki67 and functional inactivation of RB1 pathway, suggesting transition from androgen-driven to proliferation-driven phenotype. Most cases presented at advanced stage with adverse radiological findings, metastasis at time of diagnosis, and high mortality. In light of their prognostic and therapeutic implications, pathologists may need to maintain a sensitive threshold for performing immunostains–in particular, Ki67 and CyclinD1–when presented with such cases in their day to day clinical practice.

Background Phyllanthus fraternus is a pantropical weed of family phyllanthaceae, mainly found in northeast India. It has been used in the folklore medicine of Manipur tribe for treating type 2 diabetes. Objective The present study was commenced to evaluate the anti-diabetic and renoprotective potential of P. fraternus (aerial parts) in alloxan-induced diabetes in rats. Materials and methods Alloxan (130 mg/kg, ip) was used for the induction of diabetes in adult male wistar rats. Animals with blood glucose level greater than 280 mg/dL were treated once daily for 14 days with various test extracts. The biochemical parameters were measured from serum on the 15th day post-treatment. Necropsy samples harvested from pancreas and kidneys were examined for histopathological changes in these organs. Results Alloxan-induced diabetes not only caused significant increases in blood glucose, triglycerides, total cholesterol, creatinine and urea levels, but also provoked high oxidative stress in pancreas and kidneys. Profound morphological injuries were observed in islets of Langerhans and kidneys of diabetic animals. Administration of methanol extract (200 and 400 mg/kg) and mother liquor (200 and 400 mg/kg) ameliorate the elevated levels of blood glucose, triglycerides, total cholesterol as well as other biochemical parameters, but highest reduction in blood glucose concentration was observed with the largest dose of ethyl acetate fraction (400 mg/kg) of P. fraternus. Histopathological examination of pancreas and kidneys also exhibited greater protection by treatment with acetate fraction (400 mg/kg). The HPLC analysis showed the presence of four polyphenols such as catechin, gallic acid, caffeic acid and ellagic acid in ethyl acetate fraction of P. fraternus during HPLC analysis. Conclusion The results suggest that polyphenols present in P. fraternus may be responsible for the anti-diabetic and renoprotective activity in rats. Such protective effects of could be mediated through flavonol-induced anti-oxidant and anti-inflammatory activities in the pancreas and kidneys.