Uncontrolled Cell Cycle Research Articles

Cancer-associated fibroblast-derived gene signature discriminates distinct prognoses by integrated single-cell and bulk RNA-seq analyses in breast cancer.

Cancer-associated fibroblasts (CAFs) are one of the most predominant cellular subpopulations in the tumor stroma and play an integral role in cancer occurrence and progression. However, the prognostic role of CAFs in breast cancer remains poorly understood. We identified a number of CAF-related biomarkers in breast cancer by combining single-cell and bulk RNA-seq analyses. Based on univariate Cox regression as well as Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, a novel CAF-associated prognostic model was developed. Breast cancer patients were grouped according to the median risk score and further analyzed for outcome, clinical characteristic, pathway activity, genomic feature, immune landscape, and drug sensitivity. A total of 341 CAF-related biomarkers were identified from single-cell and bulk RNA-seq analyses. We eventually screened eight candidate prognostic genes, including CERCAM, EMP1, SDC1, PRKG1, XG, TNN, WLS, and PDLIM4, and constructed the novel CAF-related prognostic model. Grouped by the median risk score, high-risk patients showed a significantly worse prognosis and exhibited distinct pathway activities such as uncontrolled cell cycle progression, angiogenesis, and activation of glycolysis. In addition, the combined risk score and tumor mutation burden significantly improved the ability to predict patient prognosis. Importantly, patients in the high-risk group had a higher infiltration of M2 macrophages and a lower infiltration of CD8+ T cells and activated NK cells. Finally, we calculated the IC50 for a range of anticancer drugs and personalized the treatment regimen for each patient. Integrating single-cell and bulk RNA-seq analyses, we identified a list of compositive CAF-associated biomarkers and developed a novel CAF-related prognostic model for breast cancer. This robust CAF-derived gene signature acts as an excellent predictor of patient outcomes and treatment responses in breast cancer.

Discovery of novel macrocyclic derivatives as potent and selective cyclin-dependent kinase 2 inhibitors

Cyclin-dependent kinase 2 (CDK2) is a member of CDK family of kinases (CDKs) that regulate the cell cycle. Its inopportune or over-activation leads to uncontrolled cell cycle progression and drives numerous types of cancers, especially ovarian, uterine, gastric cancer, as well as those associated with amplified CCNE1 gene. However, developing selective lead compound as CDK2 inhibitors remains challenging owing to similarities in the ATP pockets among different CDKs. Herein, we described the optimization of compound 1, a novel macrocyclic inhibitor targeting CDK2/5/7/9, aiming to discover more selective and metabolically stable lead compound as CDK2 inhibitor. Molecular dynamic (MD) simulations were performed for compound 1 and 9 to gain insights into the improved selectivity against CDK5. Further optimization efforts led to compound 22, exhibiting excellent CDK2 inhibitory activity, good selectivity over other CDKs and potent cellular effects. Based on these characterizations, we propose that compound 22 holds great promise as a potential lead candidate for drug development.

The Absence of Intra-Tumoral Tertiary Lymphoid Structures is Associated with a Worse Prognosis and mTOR Signaling Activation in Hepatocellular Carcinoma with Liver Transplantation: A Multicenter Retrospective Study.

Tertiary lymphoid structure (TLS) can predict the prognosis and sensitivity of tumors to immune checkpoint inhibitors (ICIs) therapy, whether it can be noninvasively predicted by radiomics in hepatocellular carcinoma with liver transplantation (HCC-LT) has not been explored. In this study, it is found that intra-tumoral TLS abundance is significantly correlated with recurrence-free survival (RFS) and overall survival (OS). Tumor tissues with TLS are characterized by inflammatory signatures and high infiltration of antitumor immune cells, while those without TLS exhibit uncontrolled cell cycle progression and activated mTOR signaling by bulk and single-cell RNA-seq analyses. The regulators involved in mTOR signaling (RHEB and LAMTOR4) and S-phase (RFC2, PSMC2, and ORC5) are highly expressed in HCC with low TLS. In addition, the largest cohort of HCC patients is studied with available radiomics data, and a classifier is built to detect the presence of TLS in a non-invasive manner. The classifier demonstrates remarkable performance in predicting intra-tumoral TLS abundance in both training and test sets, achieving areas under receiver operating characteristic curve (AUCs) of 92.9% and 90.2% respectively. In summary, the absence of intra-tumoral TLS abundance is associated with mTOR signaling activation and uncontrolled cell cycle progression in tumor cells, indicating unfavorable prognosis in HCC-LT.

Polyporus ulleungus mycelia cultured in MEB medium produce metabolites with anticancer property.

Cancer cells are characterized by apoptosis evasion and uncontrolled cell cycle progression. To combat these characteristics, efforts have been made to find novel natural-source anticancer compounds. The aim of this work is to find new anticancer compounds in Polyporus ulleungus (P. ulleungus) mycelial culture extracts. P. ulleungus mycelium was cultured on four individual media (DYB, MEB, MYB, and PDB) and four extracts were generated from the mycelium culture media. Extracts of P. ulleungus mycelium cultured in MEB medium (pu-MEB) significantly reduced cancer cell growth by triggering apoptosis and S phase arrest. Furthermore, the anticancer effects of pu-MEB were not confined to one type of cancer. Taken together, our results confirmed that P. ulleungus mycelia cultured in MEB medium produce metabolites that exhibit anticancer properties. Development of an optimal medium for P. ulleungus mycelium through optimization of medium components will enable P. ulleungus mycelium to produce metabolites with more anticancer efficacy.

Abstract LB_C13: Development of BLX-3030, a potent, selective, orally available CDK9i shows promise in Pancreatic Ductal Adenocarcinoma (PDAC) models

Abstract Background: CDK9 (cyclin-dependent kinase 9), is a Ser/Thr kinase that plays a crucial role in regulating gene expression. It is a component of the P-TEFb complex, which controls transcription elongation by phosphorylating RNA polymerase II. Dysregulated CDK9 has been linked to cancer progression. Pharmacological CDK9 inhibition has recently emerged as a novel and promising approach for cancer therapy, particularly in exocrine pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (PNETs). PDAC and PNETs are cancer entities with a dismal prognosis, owing mainly to their resistance to chemo, radiation, and immunotherapies. Dysregulation of CDK9 activity can lead to uncontrolled cell cycle progression and tumor formation. Given the role of CDK9 in promoting PDACs progression, targeting this kinase has emerged as a potential therapeutic strategy for PDACs and PNETs where our late-breaking results of BLX-3030 demonstrated efficacy in pre-clinical tumor models. Materials and Methods: Our proprietary MolecuLernTM fragment-based design platform, in vitro cellular efficacies as a single agent or combination, FACS/apoptosis, cell migration, live-cell imaging, and immunofluorescence assays. Top compounds were evaluated for 7-day tox, PK, selectivity, Nano BRET, ADME-Tox, in vitro safety, hERG, P450, SafetyScreen44 panel, LDH-Glo assay, and KINOMEscan for selectivity. Results: Utilizing a CDK9-refined crystal structure and the MolecuLernTM, we identified novel, reversible, ATP-competitive inhibitors that exhibited potent activity in MYC-expressing pancreatic cancer cells in vitro. BLX-3030, elected from over 90 analogs demonstrated potent activity with an IC50 of 4.2 nM in inhibiting CDK9. CDKs family selectivity and target engagement NanoBRET assay results show the BLX-3030 selectivity and its on-target potency with an IC50 of 24.3 nM. BLX-3030 potently inhibited the growth of pancreatic cancer cells with IC50s ranging from 133 nM to 508 nM in 10 different cell lines. Furthermore, BLX-3030 and its analogs showed excellent PK properties in mice, rats, and dogs with an oral bioavailability of 28%, 38%, and 83%, respectively. BLX-3030 has a low clearance and >3 hours half-life in rodents and canine species. The effect of BLX-3030 in vivo PDAC models including ex vivo results for the levels of CDK9, pCDK9, c-MYC, and cleaved Caspase 3 in tumor tissues will be discussed. Based on these pre-clinical results, BLX-3030 was nominated as a candidate with additional efficacy and safety data supporting IND-enabling studies Conclusion: In summary, BLX-3030 is a potent CDK9i that displayed potent antitumor activity in pancreatic cancer models, with its promising safety, PK, and developable characteristics leading us to select and nominate as clinical candidates. Our late-breaking pre-clinical results from our in vivo study in pancreatic cancer tumor models, including 7-day safety, tolerability, and toxicokineCDK9tic results received are supportive for our planned ND enabling studies and future clinical trials will be presented. Citation Format: Kyle Medley, Zhaoliang Li, Chenyu Lin, Yesenia Barrera-Millan, Lynne Kelley, Haiyong Han, Hariprasad Vankayalapati, David J Bearss. Development of BLX-3030, a potent, selective, orally available CDK9i shows promise in Pancreatic Ductal Adenocarcinoma (PDAC) models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C13.

A promising new cancer marker: Long noncoding RNA EGFR-AS1.

Cancer consists of a group of diseases with the salient properties of an uncontrolled cell cycle, metastasis, and evasion of the immune response, mainly driven by the genomic instability of somatic cells and the physicochemical environment. Long noncoding RNAs (lncRNAs) are defined as noncoding RNAs with a length of more than 200 nucleotides. LncRNA dysregulation participates in diverse disease types and is tightly associated with patient clinical features, such as age, disease stage, and prognosis. In addition, an increasing number of lncRNAs have been confirmed to regulate a series of biological and pathological processes through numerous mechanisms. The lncRNA epidermal growth factor receptor antisense RNA 1 (EGFR-AS1) was recently discovered to be aberrantly expressed in many types of diseases, particularly in cancers. A high level of EGFR-AS1 was demonstrated to correlate with multiple patient clinical characteristics. More importantly, EGFR-AS1 was found to be involved in the mediation of various cellular activities, including cell proliferation, invasion, migration, chemosensitivity, and stemness. Therefore, EGFR-AS1 is a promising marker for cancer management. In this review, we introduce the expression profile, molecular mechanisms, biological functions, and clinical value of EGFR-AS1 in cancers.

Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon.

Uncontrolled proliferative signals and cell cycle dysregulation due to genomic or functional alterations are important drivers of the expansion of undifferentiated blast cells in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells. Therefore, they are largely studied as potential therapeutic targets in the field. We here present the most recent advancements in the evaluation of novel compounds targeting cell cycle proteins or oncogenic mechanisms, including those showing an antiproliferative effect in acute leukemia, independently of the identification of a specific target. Several new kinase inhibitors have been synthesized that showed effectiveness in a nanomolar to micromolar concentration range as inhibitors of FLT3 and its mutant forms, a highly attractive therapeutic target due to its driver role in a significant fraction of AML cases. Moreover, we introduce novel molecules functioning as microtubule-depolymerizing or P53-restoring agents, G-quadruplex-stabilizing molecules and CDK2, CHK1, PI3Kδ, STAT5, BRD4 and BRPF1 inhibitors. We here discuss their mechanisms of action, including the downstream intracellular changes induced by in vitro treatment, hematopoietic toxicity, in vivo bio-availability and efficacy in murine xenograft models. The promising activity profile demonstrated by some of these candidates deserves further development towards clinical investigation.

Beyond the Lab: What We Can Learn about Cancer from Wild and Domestic Animals.

Cancer research has benefited immensely from the use of animal models. Several genetic tools accessible in rodent models have provided valuable insight into cellular and molecular mechanisms linked to cancer development or metastasis and various lines are available. However, at the same time, it is important to accompany these findings with those from alternative or non-model animals to offer new perspectives into the understanding of tumor development, prevention, and treatment. In this review, we first discuss animals characterized by little or no tumor development. Cancer incidence in small animals, such as the naked mole rat, blind mole rat and bats have been reported as almost negligible and tumor development may be inhibited by increased defense and repair mechanisms, altered cell cycle signaling and reduced rates of cell migration to avoid tumor microenvironments. On the other end of the size spectrum, large animals such as elephants and whales also appear to have low overall cancer rates, possibly due to gene replicates that are involved in apoptosis and therefore can inhibit uncontrolled cell cycle progression. While it is important to determine the mechanisms that lead to cancer protection in these animals, we can also take advantage of other animals that are highly susceptible to cancer, especially those which develop tumors similar to humans, such as carnivores or poultry. The use of such animals does not require the transplantation of malignant cancer cells or use of oncogenic substances as they spontaneously develop tumors of similar presentation and pathophysiology to those found in humans. For example, some tumor suppressor genes are highly conserved between humans and domestic species, and various tumors develop in similar ways or because of a common environment. These animals are therefore of great interest for broadening perspectives and techniques and for gathering information on the tumor mechanisms of certain types of cancer. Here we present a detailed review of alternative and/or non-model vertebrates, that can be used at different levels of cancer research to open new perspectives and fields of action.

Circular RNA Controls Tumor Occurrence and Development via Cell Cycle Regulation.

Circular RNAs (circRNAs) participate in the occurrence and development of various diseases through different mechanisms, such as by acting as a microRNA (miRNA) sponge, interacting with RNA-binding proteins, and regulating gene transcription and protein translation. For example, the abnormal expression of specific circRNAs in tumor cells can alter key regulatory factors and the cell cycle network, resulting in cell cycle disorders and the development and metastasis of tumors. Here, we summarize the mechanisms involved in the circRNA-mediated processes that lead to uncontrolled cell cycle and tumor cell proliferation. Extensive studies investigating the abnormal expression of circRNAs in different cancer types have been conducted. The unique characteristics of circRNAs and their ability to regulate the cell cycle through diverse mechanisms is extremely valuable in tumor diagnosis, treatment, and prognosis. Our review may assist in further understanding the circRNA-mediated regulation of the cell cycle in tumors and provide insights for research on circRNA-based therapeutic strategies and biological diagnosis for cancer.

Unusually high incidence of polyomavirus JC infection in the higher grade of colorectal cancer tissues in Taiwan

IntroductionThe human JC polyomavirus (JCPyV) has been detected in colorectal cancer (CRC) tissues and is suggested to contribute to CRC tumorigenesis. The rearrangement of the JCPyV regulatory region is supposedly associated with CRC development. The progression of CRC involves the stepwise accumulation of mutations. The large tumor antigen (LT) of JCPyV can trigger uncontrolled cell cycle progression by targeting oncogenes, and tumor suppressor genes, and causing chromosome instability. Few studies have focused on the presence of JCPyV DNA in the higher grade of CRC tissues.MethodsWe collected 95 tissue blocks from samples of stages I, II, III, and IV CRC. Nested PCR targeting the regulatory region of the viral genome was performed to determine the presence of JCPyV DNA in the various stages of colorectal cancer tissues.ResultsThe nested PCR results showed that the positive rate of JCPyV DNA increased with the progression of CRC stages. The archetypal-like, non-rearrangement genotype of JCPyV with subtle mutations was the major genotype found in CRC samples.ConclusionsThis finding in our study suggests that there may be an association between JCPyV and CRC progression.

The kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancer

The activity of integrin-linked kinase (ILK) in cancerous cells is often oncogenic and associated with malignant properties, such as uncontrolled cell cycle progression and evasion from senescence. However, the role of ILK in cellular senescence in gastric cancer (GC) has not been previously examined. We generated single-cell clones of ILK knock-out using CRISPR-Cas9 in human GC lines with mesenchymal or epithelial histology. Cells with no residual ILK expression exhibited strong cellular senescence with diminished clathrin-mediated endocytosis, Surprisingly, ILK loss-induced cellular senescence appeared to be independent of its function in integrin signaling. The low dose of CPD22, a small molecule inhibitor of ILK activity-induced senescence in three GC cell lines with different histologies. Furthermore, senescent cells with ILK depletion transfected with N-terminal truncated ILK mutant remaining catalytic domains displayed the reduction of senescent phenotypes. RNA sequencing and cytokine array results revealed the enrichment of multiple pro-inflammatory signaling pathways in GC lines in the absence of ILK. Our study identified the important role and the potential mechanism of ILK in the cellular senescence of cancerous epithelial cells. The inhibition of ILK activity using small molecule compounds could have a pro-senescent effect as a therapeutic option for GC.

Abstract 1775: Scope of cell cycle inhibition in HER2+ breast cancer

Abstract Background: Proliferative signaling of the HER2- and ER-pathways converge and propagate via cyclin D and CDK4/6, leading to uncontrolled cell cycle progression and resistance to anti- HER2- and ER-targeted therapies. Purpose: We hypothesize that co-targeting HER2 and CDK4/6 will counter the uncontrolled cell cycle progression, initiate cell cycle arrest, and induce apoptosis in Rb-proficient HER2-amplified breast cancer (BC) cells. Methods: HER2+ BC cell lines (Rb-WT): BT474 (HR-positive), SKBR3 (HR-negative), and MDA-MB453 (HR-negative, PIK3CA mutated [H1047R]) were used for the study. We tested real-time proliferation, 3D-ON TOP colony formation, cell cycle inhibition, changes in mitochondrial membrane potential, and apoptosis following drug treatment as a single-agent (Ribociclib [R]/Trastuzumab [T]) or combination (R+T). Basal-level mRNA transcripts for CDK4 and CCND1 and changes in Ki67 following treatment were quantified with RT-qPCR. Cyclin D expression was evaluated in HER2+ tissue microarrays (TMA) by immunohistochemistry. The mechanistic evaluation of the critical downstream signaling nodes was performed by Western blot. Results: Basal-level mRNA transcript expression for CDK4 and CCND1 were substantially higher (relative to GAPDH) in BT474 and MDA-MB453 whereas, moderate-low expression was obtained in SKBR3. Ki67 transcriptional level was attenuated with R, and further attenuation was observed with dual agent treatment except for SKBR3, where a similar trend was conserved but of reduced intensity. Immunohistochemistry showed substantial cyclin D expression in HER2+ TMA signifying opportunities for CDK4/6 inhibitors. BT474 and MDA-MB453 had similar anti-proliferative responses to the combinatorial treatment, whereas SKBR3 showed resistance to growth inhibition. Similar to real-time proliferation, 3D-ON TOP colony formation showed a reduction in proliferative activities with the combination. The cytostatic response was primarily induced by R and did not differ significantly from the combination of treatment. BT474 and MDA-MB453 had >90% G1 phase arrest, while SKBR3 had >70% G1 phase arrest. Changes in the mitochondrial membrane potential and apoptosis were pronounced with the combination in BT474 and MDA-MB453, whereas SKBR3 did not show any significant response. Western blot showed a reduction in Rb phosphorylation (pRb Ser 780 & Ser 807/811) in all cell lines with R treatment, and further attenuation was observed with combinatorial treatment. Changes in the phospho-Akt were more evident with T and R+T combination in BT474 and MDA-MB453 over HER2-amplified/HR-negative SKBR3 cells. Conclusions: The R+T combination counteracted the proliferative signaling in the HR-positive conditions and sensitized neoplastic cells to elicit an enhanced anti-tumorigenic response irrespective of PIK3CA hotspot mutation. Citation Format: Nischal Koirala, Jennifer Aske, Xiaoqian Lin, Nandini Dey, Pradip De. Scope of cell cycle inhibition in HER2+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1775.

RNA-binding protein MEX3A controls G1/S transition via regulating the RB/E2F pathway in clear cell renal cell carcinoma

MEX3A is an RNA-binding protein that mediates mRNA decay through binding to 3′ untranslated regions. However, its role and mechanism in clear cell renal cell carcinoma remain unknown. In this study, we found that MEX3A expression was transcriptionally activated by ETS1 and upregulated in clear cell renal cell carcinoma. Silencing MEX3A markedly reduced clear cell renal cell carcinoma cell proliferation in vitro and in vivo. Inhibiting MEX3A induced G1/S cell-cycle arrest. Gene set enrichment analysis revealed that E2F targets are the central downstream pathways of MEX3A. To identify MEX3A targets, systematic screening using enhanced cross-linking and immunoprecipitation sequencing, and RNA-immunoprecipitation sequencing assays were performed. A network of 4,000 genes was identified as potential targets of MEX3A. Gene ontology analysis of upregulated genes bound by MEX3A indicated that negative regulation of the cell proliferation pathway was highly enriched. Further assays indicated that MEX3A bound to the CDKN2B 3′ untranslated region, promoting its mRNA degradation. This leads to decreased levels of CDKN2B and an uncontrolled cell cycle in clear cell renal cell carcinoma, which was confirmed by rescue experiments. Our findings revealed that MEX3A acts as a post-transcriptional regulator of abnormal cell-cycle progression in clear cell renal cell carcinoma.

Lower growth arrest-specific 5 level in endometrium is related to endometriosis via promoting cell proliferation and angiogenesis.

Long noncoding RNAs are a group of more than 200 nt, nonprotein coding RNAs, some of which are dysregulated in many pathophysiological processes including endometriosis. This study aims to clarify the roles of dysregulated growth arrest-specific 5 (GAS5) in patients with endometriosis, and unveil the underlying mechanisms. We obtained endometrium samples from 37 patients with endometriosis and 23 controls without endometriosis. Primary endometrial stromal cells (ESCs) and endothelial cells were separated from the endometrium. Levels of GAS5 were quantified using quantitative real-time polymerase chain reaction, and levels of p27, cleaved caspase-3, cleaved poly (ADP-Ribose) polymerase 1, vascular endothelial growth factor A, tissue inhibitor of metalloproteinases 3 (TIMP3), and trypsin-modified soy protein 10 were assessed by immunoblotting. Cell viability was examined using MTT assays, and the cell cycle and apoptosis were analyzed by flow cytometry. Endothelial cell tube formation capacity was assayed in vitro. GAS5 and p27 levels were found lower in the endometrium samples from patients with endometriosis. Primary ESCs from patients with endometriosis had increased viability, reduced apoptosis, and a relatively uncontrolled cell cycle. Gain- and loss-of-function studies confirmed that GAS5 regulated p27 expression in ESCs. Furthermore, GAS5 level was relatively low in primary endothelial cells from patients with endometriosis and GAS5 acted as an angiogenesis inhibitor by regulating the miR-181c-TIMP3 axis. Thus, lower GAS5 level in endometrium might be related to endometriosis by regulating cell proliferation, apoptosis, cell cycle, and angiogenesis.

CYCLONE 1: A phase 2 study of abemaciclib in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a novel hormonal agent and taxane-based chemotherapy.

TPS5086 Background: In cancer cells, the cyclin-dependent kinases 4 and 6 (CDK4 & 6)/retinoblastoma protein (Rb) pathway is commonly altered, resulting in uncontrolled cell cycle entry and proliferation. CDK4 & 6 inhibitors represent a major advance in the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC or MBC, respectively). Abemaciclib is an oral selective inhibitor of CDK4 & 6 administered on a continuous dosing schedule, approved in combination with endocrine therapy for HR+, HER2- ABC or MBC. In addition, abemaciclib is also approved by the FDA as monotherapy for HR+, HER2- ABC or MBC following endocrine therapy and prior chemotherapy in the metastatic setting. Similar to the estrogen receptor signaling pathway in breast cancer cells, there is evidence that the androgen receptor axis activates CDK4 & 6 to sustain prostate cancer cell proliferation and survival. Preclinical studies in prostate cancer cell lines and xenograft models showed that abemaciclib exhibits single agent activity by inducing cell cycle arrest and tumor growth inhibition. Clinical activity of abemaciclib in combination with abiraterone and prednisone is investigated in a randomized phase 2 study in the first-line mCRPC setting (CYCLONE 2, NCT03706365). Despite recent advances, management of heavily pretreated mCRPC remains a major clinical challenge. Herein, we hypothesize that mCRPC patients whose disease progressed after novel hormonal agents (NHA) and taxane therapies may derive therapeutic benefit from single agent abemaciclib. Methods: CYCLONE 1 is a phase 2, single-arm, multicenter study to assess the safety and efficacy of abemaciclib monotherapy in 40 patients with mCRPC progressing after ≥1 NHA and 2 taxane regimens. Patients will be enrolled at time of prostate specific antigen (PSA) or radiographic progression per PCWG3 criteria and have at least 1 measurable lesion per RECIST 1.1. Metastatic tumor tissue (fresh biopsy or archival material <12 weeks) is required at baseline for biomarker analysis. Patients will receive abemaciclib 200 mg twice daily until unacceptable adverse events or disease progression. The primary objective is investigator-assessed objective response rate (ORR). Key secondary objectives include safety, radiographic progression-free survival, overall survival, PSA response rate, time to PSA progression, time to symptomatic progression, Ki-67 expression, patient-reported outcomes, and pharmacokinetics. Assuming an ORR of 15%, the study has over 73% power to observe a response rate of at least 12.5%. Accrual began in January 2021. Clinical trial information: NCT04408924.

Dual roles of SAMHD1 in tumor development and chemoresistance to anticancer drugs.

Human sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) has been identified as a GTP or dGTP-dependent deoxynucleotide triphosphohydrolase (dNTPase) and acts as an antiviral factor against certain retroviruses and DNA viruses. Genetic mutation in SAMHD1 causes the inflammatory Aicardi-Goutières Syndrome and abnormal intracellular deoxyribonucleoside triphosphates (dNTPs) pool. At present, the role of SAMHD1 in numerous types of cancer, such as chronic lymphocytic leukemia, lung cancer and colorectal cancer, is highly studied. Furthermore, it has been found that methylation, acetylation and phosphorylation are involved in the regulation of SAMHD1 expression, and that genetic mutations can cause changes in its activities, including dNTPase activity, long interspersed element type 1 (LINE-1) suppression and DNA damage repair, which could lead to uncontrolled cell cycle progression and cancer development. In addition, SAMHD1 has been reported to have a negative regulatory role in the chemosensitivity to anticancer drugs through its dNTPase activity. The present review aimed to summarize the regulation of SAMHD1 expression in cancer and its function in tumor growth and chemotherapy sensitivity, and discussed controversial points and future directions.

Over expression of PTEN induces apoptosis and prevents cell proliferation in breast cancer cells.

The phosphatase and tensin homolog (PTEN) is a tumor suppressor lipid phosphatase frequently mutated or deleted in breast cancer cells. Loss of PTEN is associated with aberrant activation of P13K/AKT signaling pathways, which are responsible for uncontrolled cell cycle, migration and prolonged survival. Therefore, stability and functional PTEN is essential for prevention of cancer growth and migration. In the present study, we have determined the effect of PTEN over expression in apoptosis induction and cell proliferation in breast cancer cells. We showed that PTEN over expression significantly declined the cell proliferation rate during logarithmic growth phase. Furthermore, the PTEN over expression leads to the activation of mitochondrial based intrinsic apoptosis pathways, which is confirmed by the activation and over expression of caspases 9 and caspases 3. In addition, the number of apoptotic cells are significantly more in PTEN over expressed cells, where they showed more apoptotic bodies in AO-EtBr and Hoechst 33344 staining. Finally, PTEN over expressed cells showed decreased chemo resistance as chemotherapeutic drugs kill them efficiently. Therefore, our findings suggest that tumor suppressive effect of PTEN is crucial for cancer prevention and thus PTEN might be a potential target for anti-cancer drugs.

Phenolic compounds, saponins and alkaloids on cancer progression: emphasis on p53 expression and telomere length

Telomere length is correlated with cell proliferation, and cancer cells are characterized by an uncontrolled cell cycle. Being apoptosis one of the checks and balances incorporated into cells cycle, due to its characteristics, cancer cells are able to overcome this process. In particular, the tumour suppressor protein p53 loss or inactivation can lead to activation of telomerase enzyme, which can make cells unable to detect DNA damages that spurs apoptosis. Some bioactive compounds, in particular phenolic compounds, saponins and alkaloids have revealed good abilities to affect p53 expression and indirectly control the telomere length. In this sense, this review gives a key emphasis to the ability of these compounds in blocking cancer progression by acting on p53 expression and controlling telomere length. As main findings, phenolic compounds, saponins and alkaloids interfere with cancer progression by stimulating p53 expression, which can cause pro-apoptotic onset and restrict the anti-apoptotic activity, in addition to preventing telomerase enzyme activity.

Adenylate Kinase and Metabolic Signaling in Cancer Cells.

A hallmark of cancer cells is the ability to rewire their bioenergetics and metabolic signaling circuits to fuel their uncontrolled proliferation and metastasis. Adenylate kinase (AK) is the critical enzyme in the metabolic monitoring of cellular adenine nucleotide homeostasis. It also directs AK→ AMP→ AMPK signaling controlling cell cycle and proliferation, and ATP energy transfer from mitochondria to distribute energy among cellular processes. The significance of AK isoform network in the regulation of a variety of cellular processes, which include cell differentiation and motility, is rapidly growing. Adenylate kinase 2 (AK2) isoform, localized in intermembrane and intra-cristae space, is vital for mitochondria nucleotide exchange and ATP export. AK2 deficiency disrupts cell energetics, causes severe human diseases, and is embryonically lethal in mice, signifying the importance of catalyzed phosphotransfer in cellular energetics. Suppression of AK phosphotransfer and AMP generation in cancer cells and consequently signaling through AMPK could be an important factor in the initiation of cancerous transformation, unleashing uncontrolled cell cycle and growth. Evidence also builds up that shift in AK isoforms is used later by cancer cells for rewiring energy metabolism to support their high proliferation activity and tumor progression. As cell motility is an energy-consuming process, positioning of AK isoforms to increased energy consumption sites could be an essential factor to incline cancer cells to metastases. In this review, we summarize recent advances in studies of the significance of AK isoforms involved in cancer cell metabolism, metabolic signaling, metastatic potential, and a therapeutic target.

KCTD12 promotes G1/S transition of breast cancer cell through activating the AKT/FOXO1 signaling.

BackgroundSustaining proliferation is the most fundamental step for breast cancer tumor genesis. Accelerated proliferation is usually linked to the uncontrolled cell cycle. However, the internal and external factors linked to the activation of breast cancer cell cycle are still to be investigated.Methodsquantitative PCR (qPCR) and Western blotting assay were used to detect the expression of potassium channel tetramerization domain containing 12 (KCTD12) in breast cancer. MTT and colony formation assays were performed to evaluate the effect of KCTD12 on cell proliferation of breast cancer. Anchorage‐independent growth assay was used to examine the in vitro tumorigenesis of breast cancer cells. Flow cytometry assay, qPCR, and Western blotting were used to investigate the detailed mechanisms of KCTD12 on breast cancer progression.ResultsHerein, the result showed that the level of KCTD12 is significantly decreased in breast cancer tissues and cells, and lower level of KCTD12 predicts poorer survival for patients with breast cancer. Further cell function tests illustrated that downregulation of KCTD12 significantly promotes cell proliferation and in vitro tumor genesis. Besides, molecular biologic experiments showed that downregulation of KCTD12 can enhance the G1/S transition through activating the AKT/FOXO1 signaling.ConclusionOur study inferred that downregulation of KCTD12 can be a novel factor for poor prognosis in breast cancer.