Target For Anticancer Therapy Research Articles

A Sampling of Highlights from the Literature.

Macrophages can be reprogrammed to promote antitumor responses (by Noah Smith via Wikimedia Commons).Multiple factors contribute to the suppression that occurs in the tumor microenvironment (TME) and this could potentially be alleviated through various mechanisms. Chen et al. find that high potassium in the TME inhibits antitumor responses from tumor-associated macrophages (TAM) via alteration of their metabolism. Blocking this metabolic switch enables TAMs to mount effective antitumor responses. Chryplewicz et al. find that TAMs in glioma are reprogrammed to a proinflammatory phenotype, along with other antitumor remodeling of the TME and tumor vasculature, after treatment with VEGF inhibitors and imipramine (tricyclic anti-depressant). These studies provide insight into multiple mechanisms of TAM suppression and potential targets that can be used to boost antitumor responses.Chen S, …, Wang D. Cell Metab 2022 September 13. DOI:10.1016/j.cmet.2022.08.016.Chryplewicz A, …, Hanahan D. Cancer Cell 2022 September 15;40:1111–27.E9.Dietary intake can affect microbiota and immunity (by the NCI via Wikimedia Commons).Dietary intake can affect antitumor immunity and response to immunotherapy. In a prospective study, Simpson et al. evaluated dietary patterns and microbial signatures of different patient populations and how these factors related to response to neoadjuvant immune checkpoint inhibition. Distinct differences between response groups were observed not only in microbial composition but also in immune-related adverse events. Specific diets, as well as certain microbial compositions, were associated with better treatment outcomes. The data highlight the crossroads of cancer-intrinsic and -extrinsic factors with patient lifestyle, and how these factors together can shape responses to treatment.Simpson RC, …, Long GV. Nat Med 2022 September 12. DOI:10.1038/s41591-022-01965-2.Immunotherapy can overcome resistance to HER2-targeted therapy (from IrinaPav via Wikimedia Commons).HER2-specific antibodies such as trastuzumab are used to treat HER2+ breast cancer, but not all patients respond and some that do ultimately relapse. Using orthogonal approaches, including analysis of tumor tissue and transcriptomic data from trastuzumab-treated patients with HER2+ breast cancer and a fully humanized immunocompetent model of HER2+ breast cancer, Rivas et al. find that a population of TGFβ-activated cancer-associated fibroblasts (CAF) and low IL2 activity associate with trastuzumab resistance. Targeting IL2 to fibroblast activation protein-α (FAP)–expressing cells restores tumor responsiveness to trastuzumab by enhancing NK cell–mediated antibody-dependent cytotoxicity, highlighting the therapeutic potential of targeting stromal components in the tumor microenvironment.Rivas EI, …, Calon A. Nat Commun 2022 September 9;13:5310.A Treg subpopulation of CAR T cells drives therapeutic resistance (from NIH via Flickr).Using single-cell profiling methods, two groups have identified subpopulations of CD19-targeting CAR T cells with T regulatory (Treg)–cell phenotypes associated with poor response in patients with B-cell lymphoma. Good et al. find a higher proportion of circulating CD4+Helios– Treg CAR T cells in patients with progressive disease who received axicabtagene ciloleucel (axi-cel), highlighting their potential as a biomarker prognostic for progression at day 7 post infusion. Haradhvala et al. similarly identify CAR+ Treg cells in blood and infusion products for patients nonresponsive to either axi-cel or tisagenlecleucel, and validate their role in mouse models of CAR T-cell treatment. The studies provide new insight into therapeutic resistance to CAR T-cell therapy.Good Z, …, Mackall CL. Nat Med 2022 September 12;28:1860–71.Haradhvala NJ, …, Maus MV. Nat Med 2022 September 12;28:1848–59.Covalent K-Ras(G12C) inhibitor provides a new target for immunotherapy (from Rawpixel).MHC class I presentation of tumor-specific peptides derived from intracellular proteins provides a target for anticancer therapy. Zhang et al. have identified a new class of therapeutically targetable MHC class I epitopes: covalently modified intracellular proteins. K-Ras(G12C) covalently conjugated to the K-Ras(G12C)-specific inhibitor ARS1620 can undergo antigen processing and presentation on MHC class I. ARS1620-specific antibodies can recognize MHC class I–restricted ARS1620-peptides. Incorporating such an antibody into a bispecific T-cell engager (BiTE) induces T-cell responses against K-Ras(G12C) tumor cells, suggesting a new strategy for cancer immunotherapy.Zhang Z, …, Craik CS. Cancer Cell 2022 September 12;40:1060–69.e7.NK cells are key component of the antitumor immune response (from NIAID via Wikimedia Commons).Understanding the factors that regulate the maturation and function of natural killer (NK) cells is important for understanding the antitumor immune response. Imianowski et al. show that the transcriptional regulator BACH2 is expressed in developing and mature NK cells and is a negative regulator of NK-cell maturation and function, keeping NK cells quiescent under conditions of IL15 stimulation. In mice lacking BACH2 in NK cells, the NK cells show increased cytotoxicity and enhanced ability to limit metastasis to the lungs in two preclinical models. The data provide new avenues for potential therapeutic modulation of NK cell–mediated antitumor immunity.Imianowski CJ, …, Roychoudhuri R. J Exp Med 2022 September 30;219:e20211476.

Sequence driven interaction of amino acids in de-novo designed peptides determines c-Myc G-quadruplex unfolding inducing apoptosis in cancer cells

c-MYC proto-oncogene harbors a putative G-quadruplex structure (Pu27) at the NHEIII1 domain, which can shuffle between transcriptional inhibitor quadruplex and transcriptionally active duplex. In cancer cells this quadruplex destabilization is preferred and NHEIII1 domain assume a duplex topology thereby inducing c-MYC overexpression and tumorigenesis. Hence, the c-MYC quadruplex acts as an excellent target for anti-cancer therapy. Though researcher have tried to develop G-quadruplex targeted small molecules, work with G-quadruplex targeting peptides is very limited. Here we present a peptide that can bind to c-MYC quadruplex, destabilize the tetrad core, and permit the formation of a substantially different structure from the quartet core seen in the canonical G-quadruplexes. Such conformation potentially acted as a roadblock for transcription factors thereby reducing cMYC expression. This event sensitizes the cancer cell to activate apoptotic cascade via the c-MYC-VEGF-A-BCL2 axis. This study provides a detailed insight into the peptide-quadruplex interface that encourages better pharmacophore design to target dynamic quadruplex structure. We believe that our results will contribute to the development, characterization, and optimization of G-quadruplex binding peptides for potential clinical application.

Roles of LonP1 in Oral-Maxillofacial Developmental Defects and Tumors: A Novel Insight.

Recent studies have indicated a central role for LonP1 in mitochondrial function. Its physiological functions include proteolysis, acting as a molecular chaperone, binding mitochondrial DNA, and being involved in cellular respiration, cellular metabolism, and oxidative stress. Given its vital role in energy metabolism, LonP1 has been suggested to be associated with multi-system neoplasms and developmental disorders. In this study, we investigated the roles, possible mechanisms of action, and therapeutic roles of LonP1 in oral and maxillofacial tumor development. LonP1 was highly expressed in oral-maxillofacial cancers and regulated their development through a sig-naling network. LonP1 may therefore be a promising anticancer therapy target. Mutations in LONP1 have been found to be involved in the etiology of cerebral, ocular, dental, auricular, and skeletal syndrome (CODAS). Only patients carrying specific LONP1 mutations have certain dental abnormalities (delayed eruption and abnormal morphology). LonP1 is therefore a novel factor in the development of oral and maxillofacial tumors. Greater research should therefore be conducted on the diagnosis and therapy of LonP1-related diseases to further define LonP1-associated oral phenotypes and their underlying molecular mechanisms.

314P Let’s bring back old drugs to conquer resistance to KRAS G12C inhibitors in NSCLC

Once considered undruggable, mutant KRAS has recently emerged as a promising target for anticancer therapies. KRASG12C is the most common mutant isoform in NSCLCs, accounting for 41–49% of cases with G12 substitutions. In KRAS-mutant lung adenocarcinomas that have received previous anticancer therapies, treatment with a selective KRAS G12C inhibitor (sotorasib) causes partial responses in around 38 % of patients. Despite the significant therapeutic responses associated with KRAS inhibitors, their efficacy in patients has been short-lived due to the emergence of drug resistance.

ODP173 Control of Alpelisib-Induced Hyperglycemia With DPP4- Inhibitors as add on to Metformin and Insulin

Abstract Context Alpelisib is an oral phosphatidylinositol-3-kinase alpha (PI3Ka) inhibitor approved in 2019 for treatment of ER/PR+, HER2-negative advanced breast cancer. The main side effect of PI3Ka inhibition is hyperglycemia. Case A 38 year-old woman was started on alpelisib and fulvestrant therapy for Stage IV bilateral breast carcinoma (ER+, PR+, HER2-negative) with multiple distant metastases. She had previously received multiple courses of systemic therapy with palbociclib, letrozole, and everolimus, in combination with fulvestrant. She was lean (BMI 20.6 kg/m 2), had a prior history of GDM only requiring diet control, and pre-existing pre-diabetes, with a baseline FPG of 5.6 mmol/L and HbA1c of 5.9%. She developed hyperglycemia after 2 months of Alpelisib 200 mg OD (FPG 138.6 mg/dL; HbA1c 5.8%) and was started on metformin 500 mg BD. Glucose levels remained under control (fasting BG of 108-126 mg/dL) until alpelisib dose was increased to 300 mg OD. Within 6 weeks of dose increment, her fasting BG markedly increased to 324 mg/dL and HbA1c to 10%. Metformin dose was increased to 1000 mg BD, linagliptin 5 mg OD and isophane insulin at 8 units once daily, was introduced in addition to lifestyle modifications. Due to the side effects resulting in diarrhea, alpelisib was discontinued temporarily for 3 weeks before subsequent reintroduction and titration to a maximum tolerable dose of 200 mg OD. Glycemic control subsequently improved with metformin, linagliptin and titration of insulin to 14units daily, with HbA1c reduction to 6. 0% and fasting BG of 84.6 mg/dL, without any hypoglycemia. Oncological assessment showed disease response, with smaller primary tumour and stable metastatic lesions. Discussion The PI3K/AKT pathway plays a central role in cellular growth and glucose metabolism. This pathway is a potent target of anticancer therapy. In physiological glucose homeostasis, postprandial insulin secretion activates the PI3Ka pathway, subsequently upregulating glucose transporters for cellular uptake and utilization of glucose. In the phase III clinical trial (SOLAR-1), the incidence of alpelisib-induced hyperglycemia was 63.7%, and was treated with insulin sensitizers such as metformin and pioglitazone. Subsequent case series have reported effective glycemic control using very low calorie diet (VLCD), SGLT2-inhibitors and insulin therapy 1 . In our patient, linagliptin, was chosen as an adjunct therapy in addition to metformin due to its mechanism of action that address insulin resistance and favourable safety profile. We also note that the severity of alpelisib side effects appeared to be dose-dependent, as seen in the clinical trial. Conclusion We demonstrated effective control of alpelisib-induced hyperglycemia using DPP4-inhibitors as an option, in combination with metformin and insulin.

Polymer Thin Film Promotes Tumor Spheroid Formation via JAK2-STAT3 Signaling Primed by Fibronectin-Integrin α5 and Sustained by LMO2-LDB1 Complex.

Cancer stem-like cells (CSCs) are considered promising targets for anti-cancer therapy owing to their role in tumor progression. Extensive research is, therefore, being carried out on CSCs to identify potential targets for anti-cancer therapy. However, this requires the availability of patient-derived CSCs ex vivo, which remains restricted due to the low availability and diversity of CSCs. To address this limitation, a functional polymer thin-film (PTF) platform was invented to induce the transformation of cancer cells into tumorigenic spheroids. In this study, we demonstrated the functionality of a new PTF, polymer X, using a streamlined production process. Polymer X induced the formation of tumor spheroids with properties of CSCs, as revealed through the upregulated expression of CSC-related genes. Signal transducer and activator of transcription 3 (STAT3) phosphorylation in the cancer cells cultured on polymer X was upregulated by the fibronectin-integrin α5-Janus kinase 2 (JAK2) axis and maintained by the cytosolic LMO2/LBD1 complex. In addition, STAT3 signaling was critical in spheroid formation on polymer X. Our PTF platform allows the efficient generation of tumor spheroids from cancer cells, thereby overcoming the existing limitations of cancer research.

A stabilized CXCL9(74–103)-derived peptide selectively inhibits proliferation, adhesion and metastasis of tumor cells that express high levels of heparan sulfate

Glycosaminoglycans/proteoglycans (GAGs/PGs) regulate numerous molecular and cellular interactions during tumor progression, and are as such potentially interesting targets for anti-cancer therapy. We previously demonstrated that an L-amino acid GAG-binding peptide derived from CXCL9, CXCL9(74–103), acted angiostatically. Here, we tested whether a CXCL9(74–103) version fully consisting of D-amino acids, to provide protease resistance and stability, retained its anti-angiogenic properties. D-CXCL9(74–103) interfered with in vitro endothelial spheroid sprouting induced by VEGF165 or FGF-2 and with FGF-2-induced vessel formation in vivo. Moreover, we investigated the anti-tumoral activity of L- and D-CXCL9(74–103) on HCT116 colon carcinoma and B16-BL6 melanoma cells. The inhibitory effect of L- and D-CXCL9(74–103) on proliferation, adhesion and metastasis was considerably different on heparan sulfate high B16-BL6 versus chrondroitin sulfate high, but heparan sulfate low HCT116 cells. D-CXCL9(74–103), with high affinity for heparan sulfate, reduced B16-BL6 2D and 3D proliferation, adhesion to endothelial cells and metastatic lung dissemination. In contrast, treatment with D-CXCL9(74–103) had no effect on HCT116 cells, as the D-peptide bound chondroitin sulfate with low affinity. Altogether, our results stress the importance of tumoral GAGs in adhesion and metastasis and highlight the potential of a D-amino acid peptide, D-CXCL9(74–103), to interfere with growth and metastasis of heparan sulfate high tumors.

Mutation of the RelA(p65) Thr505 phosphosite disrupts the DNA replication stress response leading to CHK1 inhibitor resistance.

Mutation of the RelA(p65) Thr505 phosphosite disrupts the DNA replication stress response leading to CHK1 inhibitor resistance.

The Role of Iron in DNA and Genomic Instability in Cancer, a Target for Iron Chelators That Can Induce ROS

Iron is a key metal involved in several biological processes such as DNA replication and repair, cellular proliferation and cell cycle regulation. Excess volumes of labile iron are toxic and can lead to the production of ROS (reactive oxygen species) via Fenton chemistry. Due to this reactive nature, it can contribute to DNA damage and genomic instability. Therefore, excess iron in the labile iron pool is associated with cancer, which has made the labile iron pool a crucial target for anticancer therapy by targeting iron. This iron can be incorporated into essential enzymes such as ribonucleotide reductase (RnR). Over several decades of research, iron chelators function as more than just RnR inhibitors. Indeed, a plethora of iron chelator mechanisms can result in therapeutic properties that can target critical steps of cancer cells’ aberrant biological abilities such as proliferation, migration and metastasis. One such mechanism is the production of redox-active complexes that can produce toxic levels of ROS in cancer cells. Cancer cells are potentially more susceptible to ROS production or modulation of antioxidant levels. Understanding iron metabolism is vital in targeting cancer. For instance, Fe-S clusters have recently been shown to play crucial roles in cell signalling by ROS through their incorporation into essential DNA replication and repair enzymes. ROS can also degrade Fe-S clusters. Iron chelators that produce toxic levels of ROS, therefore, could also target Fe-S centres. Thus, the design of iron chelators is important, as this can determine if it will participate in redox cycling and produce ROS or if it is solely used to remove iron. This review focuses on alterations in cancer iron metabolism, iron’s role in genomic stability and how the design of chelators can use Fenton chemistry to their advantage to cause DNA damage in cancer cells and potentially inhibit Fe-S centres.

81P Effect of disulfide bonds and N-glycosylation on the recognition of the NaPi2b transporter by monoclonal antibodies

The search for anticancer therapy targets is the main task of oncology. One hopeful target is a membrane glycoprotein the sodium-dependent phosphate transporter NaPi2b overexpressed in ovarian carcinomas. NaPi2b is an antigen for the MX35 antibody which recognizes an epitope in the large extracellular domain (ECD) of the NaPi2b mostly in tumor but not in normal cells. The ECD contains 4 cysteines at positions 303, 322, 328, 350 and potential N-glycosylation sites at positions 295, 308, 313, 321, 335, 340.

A Different Trend of Heat Shock Proteins 90 mRNA and Protein Inhepatocellular Carcinoma Cell Line-Secreted Extracellular Vesicles

Primary Hepatocellular Carcinoma (HCC) does not usually show any symptoms at the early stage and the use of biomarkers is necessary to aid in diagnosis. Recently Extracellular Vesicles (EVs), submicron membranebound structures secreted from different cell types containing a wide variety of bioactive molecules, have increased the attention in many cancers, including HCC, becoming an auspicious candidate as biomarkers and therapy in the scenario of limited diagnostic and treatment option. Many indications have shown that heat shock proteins (Hsps) are important modulators in treatment resistance and invasion of HCC becoming attractive therapeutic targets. In particular, Hsp90a/β isoforms have been found to play critical roles in regulating the proliferation, apoptosis, and metastasis of tumor cells, suggesting for these proteins a role as targets for modern anticancer therapies. The study aimedto verify the presence of Hsp90a/β in EVs secreted by an HCC tumor cell line (HepG2) and by a non-tumorigenic hepatocyte cell line (WRL68), both at protein and mRNA levels, and to analyze their expression variations. The result showed that Hsp90s are transported by the EVs as protein but not at the mRNA level. To build new therapeutic targets using EVs or other organelles as performed on exosomes in recent studies, it is essential to evaluate the action at the pre or post-transcriptional level given their different behavior in transporting proteins or mRNA.

Clinical relevance and therapeutic aspects of professional antigen-presenting cells in lung cancer.

Lung cancer stays the preeminent cause of death worldwide. Despite recent advancements in chemotherapy, radiotherapy, and immunotherapy, the survival rate for people with advanced stages of the disease is still appalling. Moreover, there is a severe lack of reliable prognoses and indicators for classification in newly developed immunotherapies. A better understanding of immune cells is necessary to harness immune response mechanisms for therapeutic effects. Professional antigen-presenting cells are responsible for determining the fate of the immune response through the antigen processing and presentation pathway (APP). The most professional antigen-presenting cells (APC) include the dendritic cells (DC), macrophages, and B cells, which present antigens to the T-helper cells. Dendritic cells are significantly explored as a tool for immunotherapy owing to their precise ability to provoke and alter T-cell responses. Moreover, the role of tumor-associated macrophages (TAMs), an abundant leukocyte in lung cancer, is also a potential target for adjuvant anti-cancer therapies. In this review, we summarize the recent advances in our understanding of the various types of immunotherapy mapped out via professional antigen-presenting cells in lung cancer.

Oncogenic Role of ADAM32 in Hepatoblastoma: A Potential Molecular Target for Therapy.

Simple SummaryHepatoblastoma (HBL) is a rare hepatic malignancy occurring mainly in early childhood. Although recently developed treatment regimens have improved prognosis, many refractory cases still exist, and the anticancer drug cis-diamminedichloroplatinum—cisplatin—primarily used in HBL treatment often induces severe side effects. Therefore, more effective and safer therapies are needed. In this study, we demonstrate that the expression level of ADAM32 is particularly high in HBL tissue samples and is associated with poor prognosis in various cancer types through the regulation of cancer cell proliferation, stemness, migration, invasion, and acquired resistance to chemotherapy. Our results thus indicate that ADAM32 could be a promising candidate therapeutic target molecule, and provide new insights into the molecular mechanisms of HBL carcinogenesis.Outcomes of pediatric hepatoblastoma (HBL) have improved, but refractory cases still occur. More effective and safer drugs are needed that are based on molecular mechanisms. A disintegrin and metalloproteases (ADAMs) are expressed with high frequency in various human carcinomas and play an important role in cancer progression. In this study, we analyzed expression of ADAMs in HBL with a cDNA microarray dataset and found that the expression level of ADAM32 is particularly high. To investigate the role of ADAM32 in cancer, forced expression or knockdown experiments were conducted with HepG2 and HBL primary cells. Colony formation, cell migration and invasion, and cell viability were increased in HepG2 expressing ADAM32, whereas knockdown of ADAM32 induced a decrease in these cellular functions. Quantitative RT-PCR demonstrated an association between ADAM32 expression and the expression of genes related to cancer stem cells and epithelial–mesenchymal transition (EMT), suggesting a role of ADAM32 in cancer stemness and EMT. Furthermore, knockdown of ADAM32 increased cisplatin-induced apoptosis, and this effect was attenuated by a caspase-8 inhibitor, suggesting that ADAM32 plays a role in extrinsic apoptosis signaling. We conclude that ADAM32 plays a crucial role in progression of HBL, so it might be a promising molecular target in anticancer therapy.

AMBRA1 and its role as a target for anticancer therapy.

The activating molecule in Beclin1-regulated autophagy protein 1 (AMBRA1) is an intrinsically disordered protein that regulates the survival and death of cancer cells by modulating autophagy. Although the roles of autophagy in cancer are controversial and context-dependent, inhibition of autophagy under some circumstances can be a useful strategy for cancer therapy. As AMBRA1 is a pivotal autophagy-associated protein, targeting AMBRA1 similarly may be an underlying strategy for cancer therapy. Emerging evidence indicates that AMBRA1 can also inhibit cancer formation, maintenance, and progression by regulating c-MYC and cyclins, which are frequently deregulated in human cancer cells. Therefore, AMBRA1 is at the crossroad of autophagy, tumorigenesis, proliferation, and cell cycle. In this review, we focus on discussing the mechanisms of AMBRA1 in autophagy, mitophagy, and apoptosis, and particularly the roles of AMBRA1 in tumorigenesis and targeted therapy.

SP1 and NFY Regulate the Expression of PNPT1, a Gene Encoding a Mitochondrial Protein Involved in Cancer.

The Polyribonucleotide nucleotidyltransferase 1 gene (PNPT1) encodes polynucleotide phosphorylase (PNPase), a 3′-5′ exoribonuclease involved in mitochondrial RNA degradation and surveillance and RNA import into the mitochondrion. Here, we have characterized the PNPT1 promoter by in silico analysis, luciferase reporter assays, electrophoretic mobility shift assays (EMSA), chromatin immunoprecipitation (ChIP), siRNA-based mRNA silencing and RT-qPCR. We show that the Specificity protein 1 (SP1) transcription factor and Nuclear transcription factor Y (NFY) bind the PNPT1 promoter, and have a relevant role regulating the promoter activity, PNPT1 expression, and mitochondrial activity. We also found in Kaplan–Meier survival curves that a high expression of either PNPase, SP1 or NFY subunit A (NFYA) is associated with a poor prognosis in liver cancer. In summary, our results show the relevance of SP1 and NFY in PNPT1 expression, and point to SP1/NFY and PNPase as possible targets in anti-cancer therapy.

Lin28 Regulates Cancer Cell Stemness for Tumour Progression.

Simple SummaryCancer stem cells (CSCs) are a small population of tumour cells bearing stemness characteristics. They have been deemed as a root of cancer development and a promising drug target for anticancer therapy. Herein, we discuss the roles of an RNA-binding protein, Lin28, in regulating cancer cell stemness to drive tumour progression. Lin28 acts on various types of RNAs in cancer cells and regulates these RNA functions to control the expression of oncogenes. In these ways, Lin28 promotes cancer cell survival, growth, and invasion. We also discuss recent efforts in developing Lin28 inhibitors targeting CSCs in tumours.Tumours develop therapy resistance through complex mechanisms, one of which is that cancer stem cell (CSC) populations within the tumours present self-renewable capability and phenotypical plasticity to endure therapy-induced stress conditions and allow tumour progression to the therapy-resistant state. Developing therapeutic strategies to cope with CSCs requires a thorough understanding of the critical drivers and molecular mechanisms underlying the aforementioned processes. One such hub regulator of stemness is Lin28, an RNA-binding protein. Lin28 blocks the synthesis of let-7, a tumour-suppressor microRNA, and acts as a global regulator of cell differentiation and proliferation. Lin28also targets messenger RNAs and regulates protein translation. In this review, we explain the role of the Lin28/let-7 axis in establishing stemness, epithelial-to-mesenchymal transition, and glucose metabolism reprogramming. We also highlight the role of Lin28 in therapy-resistant prostate cancer progression and discuss the emergence of Lin28-targeted therapeutics and screening methods.

CDK7 is a prognostic biomarker for non-small cell lung cancer.

AimNon-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death globally despite promising progress of personalized therapy approaches. Cyclin-dependent kinase 7 (CDK7) is a kinase involved in transcription, overexpressed in a broad spectrum of cancer types and found to be associated with an unfavourable prognosis. In this study, we aimed to investigate the protein expression of CDK7 in a large cohort of NSCLC incorporating adenocarcinomas (adNSCLC) and squamous cell carcinomas (sqNSCLC) and to correlate its expression with clinicopathological data.MethodsWe performed immunohistochemical staining of CDK7 on our cohort of NSCLC including 258 adNSCLC and 101 sqNSCLC and measured protein expression via a semi-automated read out. According to the median value of CDK7 the cohort was stratified in a CDK7 high and low expressing group, respectively, and results were correlated with clinico-pathological data.ResultsCDK7 was significantly higher expressed in sqNSCLC than in adNSCLC. In the group of sqNSCLC, CDK7 expression was significantly higher in sqNSCLC with lymph node metastases than in sqNSCLC with N0 stage. We found a significantly worse overall survival and disease-free survival for patients with CDK7 high expressing NSCLC.ConclusionSince a high CDK7 expression seems to be linked with a poor prognosis it might serve as a promising novel prognostic biomarker and its assessment could be implied in future routine diagnostic workup of NSCLC samples. Considering that CDK7 inhibitors are currently tested in several trials for advanced solid malignancies, it may also be a new target for future anti-cancer therapy.

NSD2 as a Promising Target in Hematological Disorders.

Alterations of the epigenetic machinery are critically involved in cancer development and maintenance; therefore, the proteins in charge of the generation of epigenetic modifications are being actively studied as potential targets for anticancer therapies. A very important and widespread epigenetic mark is the dimethylation of Histone 3 in Lysine 36 (H3K36me2). Until recently, it was considered as merely an intermediate towards the generation of the trimethylated form, but recent data support a more specific role in many aspects of genome regulation. H3K36 dimethylation is mainly carried out by proteins of the Nuclear SET Domain (NSD) family, among which NSD2 is one of the most relevant members with a key role in normal hematopoietic development. Consequently, NSD2 is frequently altered in several types of tumors—especially in hematological malignancies. Herein, we discuss the role of NSD2 in these pathological processes, and we review the most recent findings in the development of new compounds aimed against the oncogenic forms of this novel anticancer candidate.

Proteasome Inhibitors and Their Potential Applicability in Osteosarcoma Treatment.

Simple SummaryBone cancer has seen minimal benefits in therapeutic options in the past 30 years. Proteasome inhibitors present a new avenue of research for the treatment of bone cancer. Proteasome inhibitors impair the function of the proteasome, a structure within the cell that removes unwanted and misfolded proteins. Bone cancer cells heavily rely on the proteasome to properly function and survive. Impairing the proteasome function can have detrimental consequences and lead to cell death. This review provides a thorough summary of the in vitro, in vivo, and clinical research that has explored proteasome inhibitors for the treatment of bone cancer.Osteosarcoma (OS) is the most common type of bone cancer, with ~30% of patients developing secondary/metastatic tumors. The molecular complexity of tumor metastasis and the lack of effective therapies for OS has cultivated interest in exploiting the proteasome as a molecular target for anti-cancer therapy. As our understanding towards the behavior of malignant cells expands, it is evident that cancerous cells display a greater reliance on the proteasome to maintain homeostasis and sustain efficient biological activities. This led to the development and approval of first- and second-generation proteasome inhibitors (PIs), which have improved outcomes for patients with multiple myeloma and mantle cell lymphoma. Researchers have since postulated the therapeutic potential of PIs for the treatment of OS. As such, this review aims to summarize the biological effects and latest findings from clinical trials investigating PI-based treatments for OS. Integrating PIs into current treatment regimens may better outcomes for patients diagnosed with OS.

The Role of Hypoxia-Inducible Factor Isoforms in Breast Cancer and Perspectives on Their Inhibition in Therapy.

Simple SummaryIn many types of cancers, the activity of the hypoxia-inducible factors enhances hallmarks such as suppression of the immune response, altered metabolism, angiogenesis, invasion, metastasis, and more. As a result of observing these features, HIFs became attractive targets in designing anticancer therapy. The lack of effective breast treatment based on HIFs inhibitors and the elusive role of those factors in this type of cancer raises the concern wheter targeting hypoxia-inducible factors is the right path. Results of the study on breast cancer cell lines suggest the need to consider aspects like HIF-1α versus HIF-2α isoforms inhibition, double versus singular isoform inhibition, different hormone receptors status, metastases, and perhaps different not yet investigated issues. In other words, targeting hypoxia-inducible factors in breast cancers should be preceded by a better understanding of their role in this type of cancer. The aim of this paper is to review the role, functions, and perspectives on hypoxia-inducible factors inhibition in breast cancer.Hypoxia is a common feature associated with many types of cancer. The activity of the hypoxia-inducible factors (HIFs), the critical element of response and adaptation to hypoxia, enhances cancer hallmarks such as suppression of the immune response, altered metabolism, angiogenesis, invasion, metastasis, and more. The HIF-1α and HIF-2α isoforms show similar regulation characteristics, although they are active in different types of hypoxia and can show different or even opposite effects. Breast cancers present several unique ways of non-canonical hypoxia-inducible factors activity induction, not limited to the hypoxia itself. This review summarizes different effects of HIFs activation in breast cancer, where areas such as metabolism, evasion of the immune response, cell survival and death, angiogenesis, invasion, metastasis, cancer stem cells, and hormone receptors status have been covered. The differences between HIF-1α and HIF-2α activity and their impacts are given special attention. The paper also discusses perspectives on using hypoxia-inducible factors as targets in anticancer therapy, given current knowledge acquired in molecular studies.