Types Of Human Cancer Research Articles

Progress of Clinical Studies Targeting Claudin18.2 for the Treatment of Gastric Cancer.

Claudin18.2 is a tight junction protein, highly selective, generally expressed only in normal gastric mucosal epithelial cells, which can effectively maintain the polarity of epithelial and endothelial cells, thus effectively regulating the permeability and conductance of the paracellular pathway. Abnormal expression of Claudin18.2 can occur in various primary malignant tumors, especially gastrointestinal tumors, and even in metastatic foci. It regulates its expression by activating the aPKC/MAPK/AP-1 pathway, and therefore, the Claudin18.2 protein is a pan-cancer target expressed in primary and metastatic lesions in human cancer types. Zolbetuximab (IMAB362), an antibody specific for Claudin18.2, has been successfully tested in a phase III clinical trial, and the results of the study showed that combining Zolbetuximab with chemotherapy notably extends patients' survival and is expected to be a potential first-line treatment for patients with Claudin18.2(+)/HER-2(-) gastric cancer. Here, we systematically describe the biological properties and oncogenic effects of Claudin18.2, centering on its clinical-pathological aspects and the progress of drug studies in gastric cancer, which can help to further explore its clinical value.

Abstract A026: PIN1 isomerase promotes the initiation and progression of bladder cancer through SREBP2-mediated cholesterol biosynthesis pathway

Abstract Bladder cancer, one of the most commonly diagnosed cancers worldwide, is associated with high morbidity, mortality, and a poor prognosis. The PIN1 phospho-dependent prolyl isomerase is frequently overexpressed in many human cancer types and affects tumor initiation and progression through disrupting the balance of oncoprotein and tumor suppressor protein signaling. However, the functional pSer/Thr.Pro protein substrates of PIN1 and its effects on downstream signaling in bladder carcinogenesis remain largely unknown. Phenotypically, we discovered that ablation of Pin1 in human/mouse bladder cancer cells and organoids formed from mouse primary urothelial cells resulted in decreased cell proliferation, stemness maintenance, cell invasion, migration, urothelium clearance capacity, and reduced free/total cholesterol levels in vitro. Re-expressing Pin1 in Pin1 knockout cells reversed the defects caused by lack of Pin1. Moreover, in vivo subcutaneous xenograft and allograft transplantation mouse models combined with an orthotopic implantation model were utilized to confirm a positive role for Pin1 in controlling tumor growth and potential metastasis. Therapeutically, a combination of the sulfopin PIN1 inhibitor and the simvastatin HMGCR inhibitor was shown to suppress cell proliferation in vitro and tumor growth in vivo synergistically. Mechanistically, we observed a negative enrichment of SREBP2-driven cholesterol metabolism pathways in PIN1 knockout cells via RNA-sequencing and used a suite of diverse molecular and biochemical approaches to show that PIN1 directly binds to JNK-dependent phosphorylated SREBP2 (Ser455) and vice versa. These results indicate that active cholesterol biosynthesis pathway in bladder cancer cells is regulated by PIN1-mediated isomerization and JNK-mediated phosphorylation of its key transcriptional factor SREBP2. These findings emphasize that PIN1 can act as a regulator and potential therapeutic target in bladder cancer. Citation Format: Xue Wang, Tony Hunter. PIN1 isomerase promotes the initiation and progression of bladder cancer through SREBP2-mediated cholesterol biosynthesis pathway [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A026.

Exploring the Potential Biological Activities of Pyrazole-Based Schiff Bases as Anti-Diabetic, Anti-Alzheimer's, Anti-Inflammatory, and Cytotoxic Agents: In Vitro Studies with Computational Predictions.

In this innovative research, we aim to reveal pyrazole-based Schiff bases as new multi-target agents. In this context, we re-synthesized three sets of pyrazole-based Schiff bases, 5a-f, 6a-f, and 7a-f, to evaluate their biological applications. The data from in vitro biological assays (including antioxidant and scavenging activities, anti-diabetes, anti-Alzheimer's, and anti-inflammatory properties) of the pyrazole-based Schiff bases 5a-f, 6a-f, and 7a-f showed that the six pyrazole-based Schiff bases 5a, 5d, 5e, 5f, 7a, and 7f possess the highest biological properties among the compounds evaluated. The cytotoxicity against lung (A549) and colon (Caco-2) human cancer types, as well as normal lung (WI-38) cell lines, was evaluated. The data from the cytotoxicity investigation demonstrated that the three Schiff bases 5d, 5e, and 7a are active against lung (A549) cells, while the two Schiff bases 5e and 7a exhibited the highest cytotoxicity towards colon (Caco-2) cells. Additionally, the enzymatic activities against caspase-3 and Bcl-2 of the six pyrazole-based Schiff bases 5a, 5d, 5e, 5f, 7a, and 7f were evaluated. Furthermore, we assessed the in silico absorption, distribution, metabolism, and toxicity (ADMT) properties of the more potent pyrazole-based Schiff bases. After modifying the structures of the six pyrazole-based Schiff bases, we plan to further extend the studies in the future.

Polyphyllin I ameliorates gefitinib resistance and inhibits the VEGF/VEGFR2/p38 pathway by targeting HIF-1a in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been administered as the first-line therapy for patients with EGFR mutations in LUAD, but it is almost inevitable that resistance to EGFR-TKIs therapy eventually arises. Polyphyllin I (PPI), derived from Paris polyphylla rhizomes, has been shown to have potent anti-cancer properties in a range of human cancer types including LUAD. However, the role of PPI in gefitinib resistance and the underlying mechanism remain elusive. PurposeTo evaluate the antitumor impacts of PPI on gefitinib resistance cells and investigate its molecular mechanism. MethodsCCK-8, wound healing, transwell assay, and xenograft model were performed to determine the anti-cancer effects of PPI as well as its ability to overcome gefitinib resistance. Immunoblotting, co-immunoprecipitation, phospho-RTK antibody array, qRT-PCR, and immunofluorescence were utilized to explore the mechanism by which PPI overrides gefitinib resistance. ResultsPPI inhibited cell survival, growth, and migration/invasion in both gefitinib-sensitive (PC9) and -resistant (PC9/GR) LUAD cells (IC50 at 2.0 μM). Significantly, treatment with PPI at 1.0 μM resensitized the resistant cells to gefitinib. Moreover, cell-derived xenograft experiments revealed that the combination of PPI and gefitinib overcame gefitinib resistance. The phospho-RTK array and immunoblotting analyses showed PPI significant inhibition of the VEGFR2/p38 pathway. In addition, molecular docking suggested the interaction between PPI and HIF-1α. Mechanistically, PPI reduced the protein expression of HIF-1α in both normoxia and hypoxia conditions by triggering HIF-1α degradation. Moreover, HIF-1α protein but not mRNA level was elevated in gefitinib-resistant LUAD. We further demonstrated that PPI considerably facilitated the binding of HIF-1α to VHL. ConclusionsWe present a novel discovery demonstrating that PPI effectively counteracts gefitinib resistance in LUAD by modulating the VEGF/VEGFR2/p38 pathway. Mechanistic investigations unveil that PPI facilitates the formation of the HIF-1α /VHL complex, leading to the degradation of HIF-1α and subsequent inhibition of angiogenesis. These findings uncover a previously unidentified mechanism governing HIF-1α expression in reaction to PPI, providing a promising method for therapeutic interventions targeting EGFR-TKI resistance in LUAD.

WTAP enhances the instability of SYTL1 mRNA caused by YTHDF2 in bladder cancer.

Bladder cancer (BCa) is the most frequent type of cancer in humans. The association between m6A modification and the anti-tumor effects of natural killer (NK) cells has been described in BCa. This study intended to investigate the implications of m6A regulators in modulating SYTL1 expression in BCa and the association with the anti-tumor effects of NK cells. The prognostic role of SYTL1 in BCa was investigated using bioinformatics analysis, and the correlation between SYTL1 expression and NK cells was analyzed. The effects of SYTL1 on the anti-tumor response of NK-92 cells were examined by RT-qPCR, cytotoxicity, western blot, and ELISA assays. The relationships among WTAP, YTHDF2, and SYTL1 were investigated by RT-qPCR, RIP-qPCR, ELISA, and actinomycin D treatment. Finally, the effects of WTAP and SYTL1 on BCa tumor growth and the anti-tumor response of NK cells were verified in vivo. SYTL1 was reduced in BCa tissues and had a prognostic significance, which was related to NK cell-mediated anti-tumor responses. NK-92 cells produced toxicity to BCa cells, which was further enhanced by SYTL1 overexpression in BCa cells through prompting LDH, NKG2D, NKp30, and NKp44 and IFN-γ levels. WTAP enhanced the degradation of the SYTL1 mRNA by YTHDF2. WTAP and YTHDF2 impaired the anti-tumor response of NK cells in BCa. SYTL1 inhibited the BCa progression in mice while enhancing the anti-tumor response of NK cells. WTAP inhibited the anti-tumor response of NK cells to BCa cells by promoting the degradation of SYTL1 mRNA through YTHDF2-mediated m6A methylation.

High Expression of KIFC1 in Glioma Correlates with Poor Prognosis.

Kinesin family member C1 (KIFC1), a non-essential kinesin-like motor protein, has been found to serve a crucial role in supernumerary centrosome clustering and the progression of several human cancer types. However, the role of KIFC1 in glioma has been rarely reported. Thus, the present study aimed to investigate the role of KIFC1 in glioma progression. Online bioinformatics analysis was performed to determine the association between KIFC1 expression and clinical outcomes in glioma. Immunohistochemical staining was conducted to analyze the expression levels of KIFC1 in glioma and normal brain tissues. Furthermore, KIFC1 expression was knocked in the glioma cell lines, U251 and U87MG, and the functional roles of KIFC1 in cell proliferation, invasion and migration were analyzed using cell multiplication, wound healing and Transwell invasion assays, respectively. The autophagic flux and expression levels matrix metalloproteinase-2 (MMP2) were also determined using imaging flow cytometry, western blotting and a gelation zymography assay. The results revealed that KIFC1 expression levels were significantly upregulated in glioma tissues compared with normal brain tissues, and the expression levels were positively associated with tumor grade. Patients with glioma with low KIFC1 expression levels had a more favorable prognosis compared with patients with high KIFC1 expression levels. In vitro, KIFC1 knockdown not only inhibited the proliferation, migration and invasion of glioma cells, but also increased the autophagic flux and downregulated the expression levels of MMP2. Upregulation of KIFC1 expression may promote glioma progression and KIFC1 may serve as a potential prognostic biomarker and possible therapeutic target for glioma.

VDR is a potential prognostic biomarker and positively correlated with immune infiltration: a comprehensive pan-cancer analysis with experimental verification.

The vitamin D receptor (VDR) is a transcription factor that mediates a variety of biological functions of 1,25-dihydroxyvitamin D3. Although there is growing evidence of cytological and animal studies supporting the suppressive role of VDR in cancers, the conclusion is still controversial in human cancers and no systematic pan-cancer analysis of VDR is available. We explored the relationships between VDR expression and prognosis, immune infiltration, tumor microenvironment, or gene set enrichment analysis (GSEA) in 33 types of human cancers based on multiple public databases and R software. Meanwhile, the expression and role of VDR were experimentally validated in papillary thyroid cancer (PTC). VDR expression decreased in 8 types and increased in 12 types of cancer compared with normal tissues. Increased expression of VDR was associated with either good or poor prognosis in 13 cancer types. VDR expression was positively correlated with the infiltration of cancer-associated fibroblasts, macrophages, or neutrophils in 20, 12, and 10 cancer types respectively and this correlation was experimentally validated in PTC. Increased VDR expression was associated with increased percentage of stromal or immune components in tumor microenvironment (TME) in 24 cancer types. VDR positively and negatively correlated genes were enriched in immune cell function and energy metabolism pathways, respectively, in the top 9 highly lethal tumors. Additionally, VDR expression was increased in PTC and inhibited cell proliferation and migration. In conclusion, VDR is a potential prognostic biomarker and positively correlated with immune infiltration as well as stromal or immune components in TME in multiple human cancers.

Bioaccessibility of bioactive compounds present in Persea americana Mill. seed ingredient during oral-gastric digestion with antibacterial capacity against Helicobacter pylori

Ethnopharmacological relevanceIn ancient Mexican cultures, the Persea americana Mill seed has been used against gastrointestinal diseases, due to high concentrations of bioactive compounds. According to Traditional Mexican Medicine, P. americana seed aqueous infusion is used against roundworms, intestinal worms, parasites, and gastrointestinal problems, in a dose taken over three or four days. In addition, Mexican Society of Natural History indicates the traditional use of P. americana seed powder as an antiparasitic, and antibacterial. On the other hand, Helicobacter pylori infection is a factor associated with the development of gastric disease, peptic ulcers as well as some types of gastric lymphomas and gastric cancer in humans; in this way is necessary scientific evidence about P. americana seed effect in gastrointestinal disease. Aim of the studyThe work aimed to evaluate bioactive compounds bioaccessibility and antimicrobial potential against Helicobacter pylori during oral-gastric digestion in vitro of food ingredient from Persea americana Mill. seed and elucidate the possible action mechanism using in silico tools. Materials and methodsInitially, P. americana seed oil and aqueous extract of P. americana seed were obtained using ultrasound and maceration respectively, and the food ingredient from P. americana seed was obtained. The samples underwent oral-gastric digestions by the INFOGEST method, to continue identifying and quantifying the bioactive compounds by HPLC-DAD and GC-MS. The anti-Helicobacter pylori activity determination were used fourteen Helicobacter pylori clinical strains and reference strains by Susceptibility testing by Minimal Inhibition Concentration, Kinetics of Growth Inhibition of H. pylori, Urease Inhibitory Kinetic. Finally, to elucidate a possible action mechanism used in silico tools (Software AutoDock 4.2.6 and BioVia Discovery v.19.1.0.1.18287). ResultsThe lipophilic fraction of P. americana seed detected oleic acid, linoleic acid, and avocadenofuran compounds, and the phenolic fraction showed the presence of catechin, rutin, ellagic, and chlorogenic acid, among others. Phenolic compounds conformational changes during oral-gastric digestion due to mechanical and acid hydrolysis, while lipophilic compounds showed a 20% increase in the gastric phase. Persea americana Mill. seed ingredient (3.08 μg/mL) showed total in vitro inhibition of clinical and reference strains of H. pylori, likewise, the lipophilic fraction had a lower inhibition concentration (2.59 μg/mL) regardless of the strains. Among the mechanisms found in silico, inhibition of target proteins such as CagA, BabA, and MUC5 were observed, as virulence factors involving adherence and bacterial pathogenicity. ConclusionsThis research provides evidence that food ingredient from P. americana seed has antimicrobial in vitro potential against H. pylori clinical strains, through phenolic and mainly lipophilic compounds, opening new scientific evidence that supports the P. americana seed's traditional use.

HER2 Overexpression in Periampullary Tumors According to Anatomical and Histological Classification-A Systematic Review.

Pancreatic cancer is one of the most aggressive, heterogeneous, and fatal types of human cancer; therefore, more effective therapeutic drugs are urgently needed. Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been identified as a cornerstone in this pathology. The aim of this review is to identify HER2 membrane overexpression in relation to pancreatic cancer pathways that can be used in order to develop a targeted therapy. After searching the keywords, 174 articles were found during a time span of 10 years, between 2013 and 2023, but only twelve scientific papers were qualified for this investigation. The new era of biomolecular research found a significant relationship between HER2 overexpression and pancreatic cancer cells in 25-30% of cases. The variables are dependent on tumor-derived cells, with differences in receptor overexpression between PDAC (pancreatic ductal adenocarcinoma), BTC (biliary tract cancer), ampullary carcinoma, and PNETs (pancreatic neuroendocrine tumors). HER2 overexpression is frequently encountered in human pancreatic carcinoma cell lines, and the ERBB family is one of the targets in the near future of therapy, with good results in phase I, II, and III studies evaluating downregulation and tumor downstaging, respectively.

Identification of genes that promote PI3K pathway activation and prostate tumour formation

We have performed a functional in vivo mutagenesis screen to identify genes that, when altered, cooperate with a heterozygous Pten mutation to promote prostate tumour formation. Two genes, Bzw2 and Eif5a2, which have been implicated in the process of protein translation, were selected for further validation. Using prostate organoid models, we show that either Bzw2 downregulation or EIF5A2 overexpression leads to increased organoid size and in vivo prostate growth. We show that both genes impact the PI3K pathway and drive a sustained increase in phospho-AKT expression, with PTEN protein levels reduced in both models. Mechanistic studies reveal that EIF5A2 is directly implicated in PTEN protein translation. Analysis of patient datasets identified EIF5A2 amplifications in many types of human cancer, including the prostate. Human prostate cancer samples in two independent cohorts showed a correlation between increased levels of EIF5A2 and upregulation of a PI3K pathway gene signature. Consistent with this, organoids with high levels of EIF5A2 were sensitive to AKT inhibitors. Our study identified novel genes that promote prostate cancer formation through upregulation of the PI3K pathway, predicting a strategy to treat patients with genetic aberrations in these genes particularly relevant for EIF5A2 amplified tumours.

FBXO43 promotes cell cycle progression in cancer cells through stabilizing SKP2

FBXO43 is a member of the FBXO subfamily of F-box proteins, known to be a regulatory hub during meiosis. A body of data showed that FBXO43 is overexpressed in a number of human cancers. However, whether and how FBXO43 affects cell cycle progression and growth of cancer cells remain elusive. In this study, we provide first piece of evidence, showing a pivotal role of FBXO43 in cell cycle progression and growth of cancer cells. Specifically, FBXO43 acts as a positive cell cycle regulator with an oncogenic activity in variety types of human cancer, including non-small cell lung cancer, hepatocellular carcinoma and sarcoma. Mechanistically, FBXO43 interacts with phosphorylated SKP2 induced by AKT1, leading to reduced SKP2 auto-ubiquitylation and subsequent proteasome degradation. Taken together, our study demonstrates that FBXO43 promotes cell cycle progression by stabilizing SKP2, and FBXO43 could serve as a potential anti-cancer target.

Abstract CT056: Development of a novel next-generation RET inhibitor

Abstract Oncogenic RET alterations confer constitutive activation in multiple types of human cancers. Two first-generation selective RET inhibitors selpercatinib and pralsetinib have been approved for patients with RET-driven solid tumors including non-small cell lung cancer (NSCLC) and thyroid cancer. However, critical unmet medical needs remain due to drug resistance caused by RET mutations in patients treated with the first-generation RET inhibitors. To address this emerging clinical issue, we discovered a highly potent and selective RET inhibitor with novel chemical scaffold through structure-based drug design, APS03118. Preclinical studies showed APS03118 had stronger in vitro and in vivo biological activity than the first-generation RET inhibitors targeting a broad range of RET fusions and mutations. Importantly, APS03118 was highly potent against a series of resistant RET mutations including the solvent front mutations RET G810C/R/S (IC50 0.04-5.72 nM) and gatekeeper mutations RET V804E/L/M (IC50 0.04-1.36 nM). Off-target screen analysis using the 468-kinase panel demonstrated APS03118 was highly selective for RET. APS03118 was orally bioavailable with good ADME and PK properties and markedly suppressed tumor growth in various RET-driven mouse xenograft tumor models (tumor growth inhibition 87-108% at 10-30 mg/kg BID). In addition, APS03118 exhibited excellent brain penetrating properties with strong efficacy in the in vivo orthotopic brain tumor model. GLP toxicity studies showed acceptable safety profiles. APS03118 received IND approval from both US FDA and China NMPA, and was granted the fast-track designation by FDA. We recently achieved First-in-Human milestone for APS03118 and the Ph 1 clinical trial is ongoing. As of January 5, 2024, three dose levels have been tested. Plasma exposure of APS03118 increased proportionally following single and repeated administration of APS03118 at different doses. APS03118 was well tolerated in NSCLC and thyroid cancer patients harboring RET fusions or mutations relapsed on the chemotherapy, multi-kinase inhibitor and first-generation RET inhibitor therapy. In addition to the favorable safety profiles, we observed sign of efficacy in the RET altered cancer patients in response to APS03118 treatment even in the early clinical trial testing. Partial response and stable disease were observed in patients 2-4 months after administration of APS03118 and dose limiting toxicity (DLT) dose has not been reached. Dose escalation for APS03118 is continuing. Taken together, APS03118 is a novel highly potent and selective next-generation RET inhibitor overcoming resistance following treatment with the first-generation RET inhibitors. APS03118 warrants further clinical development. Citation Format: Jun Zhong, Ruxue Xiao, Wenya Xie, Minchun Chen, Xiaohu Chen, Hao Wang, Yongbo Liu, Qin Gao, Xiupeng Wang, Zongbao Wang, Qian Chen, Jing Yang, Yizhe Ji, Yuxun Wang. Development of a novel next-generation RET inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT056.

Discovery of a novel small-molecule activator of SIRT3 that inhibits cell proliferation and migration by apoptosis and autophagy-dependent cell death pathways in colorectal cancer

Colorectal cancer (CRC) is well known as a prevalent malignancy affecting the digestive tract, yet its precise etiological determinants remain to be elusive. Accordingly, identifying specific molecular targets for colorectal cancer and predicting potential malignant tumor behavior are potential strategies for therapeutic interventions. Of note, apoptosis (type I programmed cell death) has been widely reported to play a pivotal role in tumorigenesis by exerting a suppressive effect on cancer development. Moreover, autophagy-dependent cell death (type II programmed cell death) has been implicated in different types of human cancers. Thus, investigating the molecular mechanisms underlying apoptosis and autophagy-dependent cell death is paramount in treatment modalities of colorectal cancer. In this study, we uncovered that a new small-molecule activator of SIRT3, named MY-13, triggered both autophagy-dependent cell death and apoptosis by modulating the SIRT3/Hsp90/AKT signaling pathway. Consequently, this compound inhibited tumor cell proliferation and migration in RKO and HCT-116 cell lines. Moreover, we further demonstrated that the small-molecule activator significantly suppressed tumor growth in vivo. In conclusion, these findings demonstrate that the novel small-molecule activator of SIRT3 may hold a therapeutic potential as a drug candidate in colorectal cancer.

Sample-Wise and Gene-Wise Comparisons Confirm a Greater Similarity of RNA and Protein Expression Data at the Level of Molecular Pathways and Suggest an Approach for the Data Quality Check in High-Throughput Expression Databases.

Identification of genes and molecular pathways with congruent profiles in the proteomic and transcriptomic datasets may result in the discovery of promising transcriptomic biomarkers that would be more relevant to phenotypic changes. In this study, we conducted comparative analysis of 943 paired RNA and proteomic profiles obtained for the same samples of seven human cancer types from The Cancer Genome Atlas (TCGA) and NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) [two major open human cancer proteomic and transcriptomic databases] that included 15,112 protein-coding genes and 1611 molecular pathways. Overall, our findings demonstrated statistically significant improvement of the congruence between RNA and proteomic profiles when performing analysis at the level of molecular pathways rather than at the level of individual gene products. Transition to the molecular pathway level of data analysis increased the correlation to 0.19-0.57 (Pearson) and 0.14-057 (Spearman), or 2-3-fold for some cancer types. Evaluating the gain of the correlation upon transition to the data analysis the pathway level can be used to refine the omics data by identifying outliers that can be excluded from the comparison of RNA and proteomic profiles. We suggest using sample- and gene-wise correlations for individual genes and molecular pathways as a measure of quality of RNA/protein paired molecular data. We also provide a database of human genes, molecular pathways, and samples related to the correlation between RNA and protein products to facilitate an exploration of new cancer transcriptomic biomarkers and molecular mechanisms at different levels of human gene expression.

Discovery of CBPD-409 as a Highly Potent, Selective, and Orally Efficacious CBP/p300 PROTAC Degrader for the Treatment of Advanced Prostate Cancer.

CBP/p300 are critical transcriptional coactivators of the androgen receptor (AR) and are promising cancer therapeutic targets. Herein, we report the discovery of highly potent, selective, and orally bioavailable CBP/p300 degraders using the PROTAC technology with CBPD-409 being the most promising compound. CBPD-409 induces robust CBP/p300 degradation with DC50 0.2-0.4 nM and displays strong antiproliferative effects with IC50 1.2-2.0 nM in the VCaP, LNCaP, and 22Rv1 AR+ prostate cancer cell lines. It has a favorable pharmacokinetic profile and achieves 50% of oral bioavailability in mice. A single oral administration of CBPD-409 at 1 mg/kg achieves >95% depletion of CBP/p300 proteins in the VCaP tumor tissue. CBPD-409 exhibits strong tumor growth inhibition and is much more potent and efficacious than two CBP/p300 inhibitors CCS1477 and GNE-049 and the AR antagonist Enzalutamide. CBPD-409 is a promising CBP/p300 degrader for further extensive evaluations for the treatment of advanced prostate cancer and other types of human cancers.

Abstract 5417: PHGDH expression level impacts tumorigenesis and metastasis in human breast cancer

Abstract Background: Phosphoglycerate dehydrogenase (PHGDH) is a metabolic enzyme, which is associated with the first step of serine synthesis. The gene encoding this enzyme is often elevated in some types of human cancer, including breast cancer. There are some researches that High-PHGDH expression promotes cancer cell proliferation and tumorigenesis. However, latest study showed that although breast tumors with high expression levels of PHGDH had more possibility to undergo primary-tumor growth, were less likely to metastasize than tumors with low expression of PHGDH by using mouse cell derived mouse models and PDX models. Nevertheless, the applicability of these outcomes to human breast cancer cell lines remains uncertain. Methods: The survival analysis according to PHGDH mRNA expression was analyzed in METABRIC datasets of breast cancer and the whole-transcriptome sequencing data of 120 breast cancer patients. To investigate the effect of PHGDH in human TNBC cell lines, PHGDH overexpressing MDA-MB-231 cell lines and PHGDH knockdown MDA-MB-468 cell lines were established. Subsequent functional experiments were performed to explore the influence of PHGDH on breast cancer tumorigenesis and metastasis. Results: In the analysis using METABRIC datasets, overall survival and disease-free survival were reduced in patients with high PHGDH expression and basal type breast cancer showed the highest mRNA level of PHGDH. Using whole-transcriptome sequencing data of 120 breast cancer patients, we also found PHGDH expression level was higher in cancer tissue(n=120) than normal tissue(n=90). In particular, triple-negative breast cancer indicated higher PHGDH level than luminal type breast cancer. We also used this data to perform analysis of overall survival, disease-free survival, metastasis free survival of non-TNBC patient and it resulted in reducing survival rate when patient showed high-PHGDH expression. However, TNBC patients demonstrated diametrical results in the identical analysis. We examined the impact of PHGDH overexpression in MDA-MB-231 cells and PHGDH knockdown in MDA-MB-468 cells, observing increased proliferation and decreased migration in breast cancer cells with elevated PHGDH levels. Conversely, PHGDH knockdown exhibited opposing effects. Subsequently analysis of markers associated with epithelial-mesenchymal transition revealed a correlation with PHGDH expression. Conclusions: Our data suggest that a potential role for PHGDH in breast cancer as a marker of reduced survival in triple-negative breast cancer, and as a regulator of cancer cell proliferation and metastasis. Citation Format: Jihong Baik, Juhee Kim, Sangeun Lee, Ayoung Park, Kyoungseob Shin, Sunghoon Kwon, Hanbyoel Lee, Wonshik Han. PHGDH expression level impacts tumorigenesis and metastasis in human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5417.

Abstract 1980: Validation of a novel Type II HER2 inhibitor through preclinical studies across various cancer models

Abstract HER2 activation through amplification, overexpression or mutation drives many types of human cancers, and has been the target of several therapeutic approaches. The demonstration of clinical benefit of available pan-ERBB and HER2 inhibitors has been hampered by the dose-limiting side effects from their collateral or residual EGFR inhibition. Here we present IAM1363 (also known as ENT-H1), a highly potent and selective irreversible inhibitor of both HER2 wild-type and HER2 oncogenic mutants. IAM1363 binds to HER2 in a type II DFG-out conformation, the only example reported to date for this target. This binding mechanism underlies its strong interactions with HER2, including N-terminally truncated HER2 (p95HER2) and HER2 kinase domain mutants, with cellular IC50s in the low nanomolar range, while sparing WT EGFR. Oral administration of IAM1363 in mice led to tumor regression (TR) in a diverse set of HER2-driven tumor models at levels well below the maximum tolerated dose (MTD). Importantly, strong in vivo efficacy was observed in tumor models that exhibited resistance to the existing HER2-targeting agents. For example, in a p95HER2 xenograft model, IAM1363 caused significant TR, including complete responses, at 100 mg/kg dose, whereas tucatinib achieved at best tumor stasis at MTD and T-DXd showed marginal effect. Besides HER2 truncation, co-occurring EGFR and other receptor tyrosine kinase (RTK) amplification or overexpression can also lead to resistance to HER2-directed treatments. IAM1363 was tested in xenograft models using HER2-amplified/EGFR-high cell lines HCC1954 and SKOV3, and demonstrated robust TRs. Even more strikingly, IAM1363 led to TR in the HCC827 human lung cancer xenograft model with mid-level HER2, and high levels of EGFR and MET expression. The resistance combatting effect of IAM1363 goes beyond co-occurring RTK-mediated mechanism as IAM1363 also showed dose-dependent TR in KYSE410, a human esophageal squamous cancer xenograft model that harbors the KRAS G12C mutation and HER2 amplification. Taken together, IAM1363 represents a promising clinical candidate for the treatment of HER2-driven tumors. Its unique binding mechanism and potent pan-HER2 activity overcome multiple resistance mechanisms, and its strong EGFR avoidance widens the safety margin. Additionally, IAM1363 was found to be consistently enriched in xenograft tumors that had moderate to high HER2 expression levels, and those with HER2 activating mutations. This distinctive pharmacokinetic property facilitates optimal target engagement in tumors, including those occurring in the brain, while minimizing potential systemic side effects. Citation Format: Lana Kulyk, Kelly Chen, Iriny Botrous, Chunmei Zhao, Chang Zhao, Michael Maestre, Shawn Wright, Joseph Dennis, Jeeyoung Park, Abby Adams, Wallace Derricotte, Shane Yost, Mary L. Anderson, Fred Manby, Tom Miller, Chao Zhang, Laurent Gomez, Zhongdong Huang. Validation of a novel Type II HER2 inhibitor through preclinical studies across various cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1980.

Abstract 4661: A dual degrader of HER2 and EGFR obliterates oncogenic signaling, overcomes therapy resistance, and inhibits metastatic lesions in HER2-positive breast cancer models

Abstract Background: HER2 is an oncogenic receptor tyrosine kinase (RTK) implicated in several types of human cancer. It is strongly expressed in about 20% of breast cancer (BC), known as HER2-positive BC (HER2+ BC), due to gene amplification. HER2 amplification or overexpression is a strong predictor of poor disease prognosis. HER2-targeted therapies are the linchpin of treating HER2+ BC. However, drug resistance is common. The main resistance mechanism is unknown. We exploited cell lines and mouse models (orthotopic patient-derived xenografts, and metastatic lesions in the brain and lung of therapy-resistant HER2+ BC) for experiments of genetic and pharmacologic depletion of HER2 and its family member EGFR, analysis of RTKs and no-RTKs, and evaluation of cell and tumor growth, to delineate the mechanism of HER2+ BC resistance to HER2 inhibitors and assess the therapeutic activity of PEPDG278D. PEPDG278D, a recombinant human protein, is the first-in-class dual degrader of HER2 and EGFR. Results: Trastuzumab-resistant HER2+ BC cells and tumors are highly vulnerable to targeted degradation of HER2 and EGFR. Trastuzumab is the most commonly used HER2 inhibitor in the clinic. Targeted degradation of HER2 and EGFR by PEPDG278D, which binds to their extracellular domains, causes extensive inhibition of oncogenic signaling proteins in HER2+ BC cells resistant to trastuzumab. This is accompanied by strong growth inhibition of cultured cells, orthotopic patient-derived xenografts, and metastatic lesions in the brain and lung of trastuzumab-resistant HER2+ BC. siRNA knockdown shows that eliminating both HER2 and EGFR is important to maximize therapeutic outcome. Collectively, our results reveal the key vulnerability of trastuzumab-resistant HER2+ BC and shows a promising strategy that overcomes trastuzumab resistance by targeting this vulnerability. Conclusions & Therapeutic Relevance: This study identifies a key therapeutic vulnerability of drug-resistant HER2+ BC and shows that an agent that targets this vulnerability is highly effective in overcoming drug resistance in this disease. The findings provide new insights and innovations to advance treatment of drug-resistant HER2+ BC that remains an unmet problem. Citation Format: Lu Yang, Arup Bhattacharya, Darrell Peterson, Yun Li, Xiaozhuo Liu, Elisabetta Marangoni, Valentina Robila, Yuesheng Zhang. A dual degrader of HER2 and EGFR obliterates oncogenic signaling, overcomes therapy resistance, and inhibits metastatic lesions in HER2-positive breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4661.

Abstract 3879: Development of potent, highly selective and efficacious SMARCA2 degraders

Abstract In human lung, melanoma and other types of human cancers, the mammalian SWItch/Sucrose Non-Fermentable (SWI/SNF) helicase SMARCA4 is frequently mutated, which leads to inactivation of its functions. SMARCA2, a close homologous protein of SMARCA4, is an attractive synthetic lethality target for human cancers with SMARCA4 deficiency. Herein, we report the discovery and biological evaluation of potent, highly selective and efficacious SMARCA2 PROTAC degraders exemplified by UM-SMD-3236. UM-SMD-3236 has a DC50 value of <1 nM in inducing degradation of SMARCA2 in cells and demonstrates >400-fold selectivity over SMARCA4 protein. Of significance, while UM-SMD-3236 achieves a Dmax of >95% against SMARCA2, it shows a Dmax of 50% against SMARCA4 in cells. In vivo, a single intravenous dose of UM-SMD-3236 attains 85-93% of SMARCA2 depletion in tumor tissues for 7 days, while showing no reduction of the SMARCA4 protein. Weekly intravenous administration of UM-SMD-3236 is highly effective in inhibition of tumor growth in SMARCA4 deficient xenograft models of human cancer. Importantly, UM-SMD-3236 shows no signs of toxicity in mice at highly efficacious doses. UM-SMD-3236 represents a highly promising SMARCA2 degrader for extensive evaluation as a potential new therapy for the treatment of SMARCA4-deficient human cancers.

Abstract 4504: Discovery of CBPD-409 and CBPD-268 as highly potent and orally efficacious CBP/p300 PROTAC degraders for the treatment of castration-resistant prostate cancer

Abstract Prostate cancer remains the leading cause of cancer-related death globally in men. While current AR-targeted therapies are effective for the treatment of prostate cancer and improve patient survival, resistance in patients typically develops within 18 months. CBP/p300 are AR transcriptional co-activators and are promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We developed a series of highly potent, selective, and orally efficacious CBP/p300 PROTAC degraders, with CBPD-409 being the best compound. CBPD-409 induces robust CBP/p300 degradation with DC50 0.2-0.4 nM and displays strong anti-proliferative effects with IC50 1.2-2.0 nM in VCaP, LNCaP and 22Rv1 AR+ cell lines. It has a favorable oral pharmacokinetic profile and achieves 50% of oral bioavailability in mice. A single oral administration of CBPD-409 at 1 mg/kg achieves >95% depletion of CBP/p300 proteins in the VCaP tumor tissue at 3 h and 24 h time points. CBPD-409 exhibits strong and dose/schedule-dependent tumor growth inhibition and is more potent and efficacious than two CBP/p300 inhibitors CCS1477 and GNE-049 and the AR antagonist Enzalutamide. To further improve the degradation potency and the oral bioavailability in rats, we developed a new class of CBP/p300 degraders based on our optimized CRBN ligand TX-16. Our efforts led to the discovery of CBPD-268 as an exceptionally potent, effective, and orally efficacious degrader of CBP/p300 proteins. In the VCaP, LNCaP and 22Rv1 cell lines, CBPD-268 induces consistent and robust CBP/p300 degradation with DC50 of ≤0.03 nM and Dmax >95%, leading to potent cell growth inhibition. CBPD-268 has excellent oral bioavailability in both mice and rats and has a good ADME profile. Oral administration of CBPD-268 at 0.3-3 mg/kg resulted in profound and persistent depletion of CBP and p300 proteins in tumor tissues and achieved strong antitumor activity in the VCaP and 22Rv1 xenograft tumor models in mice, including tumor regression in the VCaP tumor model. CBPD-268 was well tolerated in mice and rats and displayed a therapeutic index of >10. Taken together, CBPD-409 and CBPD-268 are highly promising CBP/p300 degraders for further extensive evaluations for the treatment of CRPC and other types of human cancers. Citation Format: Zhixiang Chen, Mi Wang, Dimin Wu, Lijie Zhao, Tianfeng Xu, Hoda Metwally, Yu Wang, Donna McEachern, Wei Jiang, Longchuan Bai, Jie Luo, Meilin Wang, Ruiting Li, John Takyi-Williams, Lu Wang, Qiuxia Li, Bo Wen, Duxin Sun, Arul M. Chinnaiyan, Shaomeng Wang. Discovery of CBPD-409 and CBPD-268 as highly potent and orally efficacious CBP/p300 PROTAC degraders for the treatment of castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4504.