Target In Tumors Research Articles

The Investigation of Somatostatin Receptors as a Potential Target in Breast Phyllodes Tumours

Background: Somatostatin receptors (SSTRs) are expressed in most neuroendocrine neoplasms, particularly in gastroenteropancreatic neuroendocrine tumours, and have been utilised as diagnostic markers and therapeutic targets. The radioiodinated somatostatin analogue 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid- Tyr3-octreotate (DOTATATE) has been employed for SSTR targeting for either diagnostic or therapeutic purposes depending on the labelling with 68Gallium or 177Lutetium, respectively. SSTR expression is reported in a subset of breast adenocarcinoma and breast neuroendocrine carcinomas; however, minimal knowledge exists regarding their expression in fibroepithelial (biphasic) breast lesions such as fibroadenoma and phyllodes tumours. Aggressive ends of the spectrum, i.e., “cystosarcoma phyllodes”, may present a management challenge with recurrences and metastases, and SSTRs could be a promising therapeutic target for these types of tumours. Methods: Gene and protein expressions of SSTRs in primary human fibroepithelial lesions of the breast are investigated using RT-PCR and immunoblotting. Localisation of the SSTR-positive cells was determined with immunohistochemistry and immunofluorescence. Results and Conclusions: Both fibroadenoma and phyllodes tumours express SSTRs. Immunohistochemical analyses suggested that this expression is in the stromal, not epithelial, component by demonstrating that SSTR stained in the areas overlapping with α-smooth muscle actin-positive myoepithelial cells around blood vessels and capillary structures. This study is the first in the literature to demonstrate SSTR positivity in mammary fibroepithelial neoplasms. Once validated, these findings may also have significant implications for managing the treatment of these tumours.

First results of migoprotafib, a potent and highly selective Src homology-2 domain-containing phosphatase 2 (SHP2) inhibitor in patients with advanced solid tumors.

Src homology-2 domain-containing phosphatase 2 (SHP2) promotes RAS-MAPK signaling and tumorigenesis and is a promising therapeutic target for multiple solid tumors. Migoprotafib is a potent and highly selective SHP2 inhibitor designed for the treatment of RAS-MAPK driven cancers, particularly in combination with other targeted agents. Here we report first-in-human study results of single agent migoprotafib in advanced solid tumor patients. We conducted a phase 1a, open-label, multi-center, dose-escalation and expansion study in adult patients with locally advanced or metastatic solid tumors. The key objectives were to evaluate safety, pharmacokinetics, pharmacodynamics (peripheral blood pERK) and preliminary anti-tumor activity. Fifty-six heavily pre-treated patients were treated with migoprotafib (10-150 mg QD). Migoprotafib had a rapid absorption rate (~0.5-2 hours) with dose-dependent increases in exposure and pathway modulation (pERK changes). The maximum tolerated dose was 100 mg and the recommended phase 2 dose (RP2D) was 60 mg daily (QD) based on safety, pharmacokinetics (PK), pharmacodynamics, and anti-tumor activity. Migoprotafib was generally well tolerated with the most frequent adverse events of diarrhea, peripheral edema, dyspnea, anemia, constipation, fatigue, AST increase and platelet count decrease. Stable disease was observed in 10 patients (18%). Migoprotafib had predictable, dose-dependent PK with an effective half-life that supports QD dosing and demonstrated promising safety, tolerability, and clinical activity at the RP2D. Further clinical testing of migoprotafib in combination with other targeted agents is warranted.

Fyn, an important molecule in the brain, is a potential therapeutic target for brain tumours.

Under normal physiological conditions, Fyn, a nonreceptor tyrosine kinase, is involved in signal transduction pathways in the nervous system and in the formation and activation of T lymphocytes. Fyn is a member of the Src family of kinases (SFKs) and plays a role in cell morphogenic transformation, motility, proliferation, and death, which in turn influences the development and progression of various cancer types. SFKs are overexpressed or hyperactive in tumours, and they are engaged in several signalling pathways that lead to tumour development. Inhibition of Fyn can enhance patient outcomes and prolong survival. Thus, Fyn is a desirable therapeutic target in a variety of tumour types. To lay the groundwork for further investigation and targeted therapy in tumours, in this article, we review the most recent findings on the function of Fyn in tumours, with an emphasis on its role in gliomas. Understanding the function of Fyn during tumourigenesis and development and in resistance to anticancer therapeutic agents can aid in the development and application of innovative medicines that specifically target this kinase, thus improving the management of cancers.

FOXP1 phosphorylation antagonizes its O-GlcNAcylation in regulating ATR activation in response to replication stress

AbstractATR signaling is essential in sensing and responding to the replication stress; as such, any defects can impair cellular function and survival. ATR itself is activated via tightly regulated mechanisms. Here, we identify FOXP1, a forkhead-box-containing transcription factor, as a regulator coordinating ATR activation. We show that, unlike its role as a transcription factor, FOXP1 functions as a scaffold and directly binds to RPA–ssDNA and ATR–ATRIP complexes, facilitating the recruitment and activation of ATR. This process is regulated by FOXP1 O-GlcNAcylation, which represses its interaction with ATR, while CHK1-mediated phosphorylation of FOXP1 inhibits its O-GlcNAcylation upon replication stress. Supporting the physiological relevance of this loop, we find pathogenic FOXP1 mutants identified in various tumor tissues with compromised ATR activation and stalled replication fork stability. We thus conclude that FOXP1 may serve as a potential chemotherapeutic target in related tumors.

Comprehensive review of signaling pathways and therapeutic targets in gastrointestinal cancers.

Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives.

Nucleic Acid Metabolism: the Key Therapeutic Target for Myeloid Tumors.

Nucleic acid analogs, including cytarabine, decitabine, and azacitidine, have significantly advanced therapeutic approaches for myeloid tumors over the past five decades. Nucleic acid metabolism is a crucial pathway driving myeloid tumorigenesis, with emerging evidence indicating that myeloid tumors are particularly dependent on the de novo nucleotide synthesis pathway, underscoring its potential as a therapeutic target. This review provides a comprehensive overview of nucleic acid metabolism, with a particular focus on de novo nucleotide synthesis. We then describe the range of clinically utilized agents targeting nucleic acid metabolism and discuss our recent findings on the non-epigenetic actions of decitabine, as well as the therapeutic effects of IMPDH inhibitors in the treatment of myeloid tumors.

HIF-3α Facilitates the Proliferation and Migration in Pancreatic Cancer by Inhibiting Autophagy Through Downregulating TP53INP2.

Pancreatic cancer is a highly aggressive malignant tumor, often diagnosed late, leading to a poor prognosis and extremely high mortality rates. In recent years, the role of cellular autophagy in tumors has become increasingly prominent, gradually becoming an important target for malignant tumors. HIF-3α is a member of HIF family with potential oncogenic function. However, the role of HIF-3α in pancreatic cancer is not clear. The present study revealed its role in pancreatic cancer by exploring the regulatory mechanism of HIF-3α on autophagy. HIF-3α was found markedly upregulated in pancreatic cancer cell lines. In HIF-3α silenced MiaPaCa-2 cells, largely declined migration distance, reduced number of invaded cells and colonies, increased number of autophagosome, downregulated p62, and upregulated Beclin1, LC3II/I, and ATG7 were observed, accompanied by elevated TP53INP2 expressions. on the contrary, in HIF-3α overexpressed PANC-1 cells, notably increased migration distance, and elevated number of invaded cells and colonies were observed, along with decreased autophagosome, upregulated p62, and downregulated Beclin1, LC3II/I, ATG7, and TP53INP2. Subsequently, HIF-3α overexpressed PANC-1 cells were transfected with TP53INP2 overexpressing vector. The influence of HIF-3α overexpression on the proliferation, migration, invasion, and autophagy was abolished by TP53INP2 overexpressing. Furthermore, HIF-3α overexpression facilitated the in vivo growth of PANC-1 cells, accompanied by the autophagy inhibition in tumor tissues, which were remarkably abolished by TP53INP2 overexpressing. Collectively, HIF-3α facilitated the proliferation and migration in pancreatic cancer by inhibiting autophagy through downregulating TP53INP2.

Chromatin Helicase CHD6 Establishes Pro-inflammatory Enhancers and is a Synthetic Lethal Target in FH-Deficient Renal Cell Carcinoma.

Fumarate hydratase (FH) deficiency causes hereditary leiomyomatosis and renal cell carcinoma (RCC). FH-deficient tumors lack effective therapeutic options. Here, we utilized an epigenetic-focused single-guide RNA library to elucidate potential drug targets in FH-deficient tumors. The screen identified chromodomain helicase DNA binding protein 6 (CHD6) as an essential regulator of the growth of FH-mutated RCC. Mechanically, FH loss induced fumarate-mediated succinylation and inactivation of KEAP1, blocking subsequent ubiquitin-proteasome degradation of CHD6. Stabilized CHD6 formed a complex with p65 to establish pro-inflammatory enhancers and thereby regulate NF-κB-mediated transcription. Moreover, CHD6 recruited mSWI/SNF ATPases to maintain chromatin accessibility at CHD6-bound enhancers. The PROTAC degrader of SMARCA2/4 AU-15330 effectively abolished structures of cis-regulatory elements bound by CHD6 and suppressed the growth of FH-mutated, but not FH-intact, RCC in vivo. Collectively, these data indicate that CHD6 is a molecular bridge between FH deficiency and pro-inflammatory enhancers assembly that endows FH-deficient tumors with epigenetic vulnerabilities.

Cell penetrable peptide nucleic acids targeting PDZK1IP1 with anti-inflammatory potential in human keratinocytes

PDZK1-interacting protein 1 (PDZK1IP1) has emerged as a potential therapeutic target for skin inflammatory diseases and epithelial tumors. This study investigates the modulation of PDZK1IP1 gene expression using peptide nucleic acids (PNAs), a class of oligonucleotide therapeutics known for their robust binding affinity to complementary nucleic acid sequences and their resistance to degradation by nucleases. To enhance water solubility and cellular permeability, modified PNA oligomers were synthesized by conjugating nucleobases with primary amine chains. A study using a fluorescein-labeled modified PNA oligomer demonstrated significantly enhanced cellular permeability in HaCaT cells compared to the unmodified PNA. These modified PNA oligomers effectively suppressed PDZK1IP1 gene expression and alleviated interferon γ (IFNγ)-induced inflammatory responses in normal human keratinocytes. These findings suggest the potential application of modified PNAs targeting PDZK1IP1 in the treatment of skin inflammatory diseases.

TRIM21-mediated ubiquitination and phosphorylation of ERK1/2 promotes cell proliferation and drug resistance in pituitary adenomas.

Pituitary adenomas (PAs) are common intracranial tumors and TRIM family plays a crucial role in cell proliferation, and therapeutic resistance of tumors. However, the role of the TRIM family in PAs is not well recognized. CRISPR screening explored the role of TRIM family in the cell proliferation and drug resistance in PAs. In vitro and in vivo experiments were performed to evaluate the effects of Tripartite Motif Containing 21 (TRIM21). RNA-sequencing, mass spectrometry, immunoprecipitation and ubiquitination experiments were performed to explore the molecular mechanism. NanoBiT assays were used to screen the drugs reducing TRIM21 expression. CRISPR-Cas9 screens identified that TRIM21 facilitated cell proliferation and drug resistance in PAs. Mechanistically, TRIM21 interacted with ERK1/2 through PRY-SPRY domain, leading to ERK1/2 K27-linked ubiquitination. The ERK1/2 ubiquitination promotes the interaction between ERK1/2 and MEK1/2, thereby facilitating the phosphorylation of ERK1/2. However, an excess presence of TRIM21 supressed the phosphorylation of ERK1/2 and cell proliferation via activating ERK1/2 negative feedback pathways. Importantly, TRIM21 was upregulated in dopamine-resistant prolactinomas and cabergoline-resistant MMQ cells. Furthermore, drug screening identified that Fimepinostat and Quisinostat, can reduce the protein levels of TRIM21, inhibit tumor progression, and increase drug sensitivity. TRIM21 may represent a therapeutic target for tumors, and inhibiting TRIM21 could be a potential strategy for tumor treatment.

Elevated type I interferon signaling defines the proliferative advantage of ARF and p53 mutant tumor cells.

The tumor suppressors p53 and ARF collaborate to prevent unwarranted cell proliferation and as such are two of the most frequently mutated genes in human cancer. Concomitant loss of functional p53 and ARF leads to massive gains in cell proliferation and transformation and is often observed in some of the most aggressive human cancer subtypes. These phenotypic gains are preceded by increased type I interferon (IFN) signaling that involves canonical STAT1 activation and a subsequent IFN-stimulated gene (ISG) signature. Here, we show that cells lacking p53 and ARF require active JAK1 to phosphorylate STAT1 on Y701 to maintain their high rate of proliferation. In fact, the use of selective JAK1 inhibitors ruxolitinib or baricitinib inhibited the induction of ISG's and the proliferation of p53 and ARF deleted cells. We identify a group of solid human tumors that lack functional p53 and ARF, show an expression signature of the upregulated type I IFN response genes, and are sensitive to selective JAK1 inhibitors. These data suggest that the type I IFN response acts as a positive driver of proliferation in the absence of p53 and ARF and, as such, presents itself as a potential therapeutic target in aggressive solid tumors.

CTNI-37. INTERIM SAFETY ANALYSIS OF THE PHASE IB/II RANDOMIZED ANTI-GLUTAMATERGIC DRUG REPURPOSING TRIAL GLUGLIO IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NCT05664464)

Abstract The advent of cancer neuroscience has significantly advanced our understanding of brain tumor biology, yet the clinical implications remain largely unexplored. Glutamate, the most abundant excitatory neurotransmitter, presents a potential therapeutic target in brain tumors. Glioblastoma cells synthesize and secrete large amounts of glutamate, driving epilepsy, neuronal death, tumor growth, and invasion. Several brain-penetrating drugs, approved for other conditions, can inhibit glutamate synthesis, secretion, and signaling. These drugs include: (i) gabapentin, an anti-seizure medication that inhibits the glutamate synthesis enzyme branched-chain amino acid transaminase 1; (ii) sulfasalazine, an anti-inflammatory drug that blocks the cystine-glutamate exchanger system Xc, reducing glutamate secretion; and (iii) memantine, a cognitive enhancer that prevents glutamate-driven, calcium-induced neuronal death and tumor cell invasion by blocking N-methyl-D-aspartate type glutamate receptors. The multi-center, open-label, parallel-group, two-arm, 1:1 randomized phase Ib/II trial GLUGLIO is investigating the efficacy of a daily oral anti-glutamatergic triple combination of gabapentin, sulfasalazine, and memantine until tumor progression, in conjunction with standard chemoradiotherapy, compared to chemoradiotherapy alone. The primary endpoint is progression-free survival at 6 months (PFS-6). A sample size of 120 patients was determined to detect an increase in PFS-6 from 50% to 70%, with 80% power, using exploratory hypothesis testing at a one-sided significance level of 10%. Secondary endpoints include overall survival, seizure-free survival, response rate, quality of life for patients and caregivers, symptom burden, cognitive functioning, tumor glutamate levels (measured by magnetic resonance spectroscopy), and the use of anti-convulsants and steroids. Each drug is dosed up to the maximum approved amount. Results from the phase Ib part of the trial, including an interim safety analysis, will be presented at the conference.

RepID as a potential biomarker and therapeutic target for lung neuroendocrine tumor

Neuroendocrine tumor (NET) is a rare malignant tumor, notably small cell lung cancer (SCLC), a type of lung neuroendocrine tumor, which has a survival rate of less than 7%. Although various biomarkers including CHGA (Chromogranin A), INSM1 (Insulinoma-associated protein 1), and SYP (Synaptophysin) are extensively used for the diagnostic testing of NET, their diverse specificities and sensitivities are acknowledged as limitations. Here, we demonstrate that RepID (Replication initiation determinant protein), a component of CRL4 (Cullin-RING ubiquitin E3 ligase 4), holds promise as a biomarker for identifying NET and SCLC. Analysis of the Cancer Cell Line Encyclopedia (CCLE) via the CellMinerCDB portal reveals a high correlation between RepID transcript levels and mRNA expression of NE signature genes. Additionally, RepID protein is highly expressed in SCLC patient tissues and a subset of SCLC cell lines. Viability analysis following treatment with pevonedistat and SZL-P1-41 in SCLC cell lines and human SCLC-organoid models indicates that RepID expression determines the sensitivity to CRL-targeting anti-cancer drugs. These findings suggest that RepID represents a novel biomarker for NET and SCLC, and insights from RepID research in these cancers could lead to innovative therapeutic strategies.

PINK1-deficiency facilitates mitochondrial iron accumulation and colon tumorigenesis

ABSTRACT Mitophagy, the process by which cells eliminate damaged mitochondria, is mediated by PINK1 (PTEN induced kinase 1). Our recent research indicates that PINK1 functions as a tumor suppressor in colorectal cancer by regulating cellular metabolism. Interestingly, PINK1 ablation activated the NLRP3 (NLR family pyrin domain containing 3) inflammasome, releasing IL1B (interleukin 1 beta). However, inhibiting the NLRP3-IL1B signaling pathway with an IL1R (interleukin 1 receptor) antagonist or NLRP3 inhibitor did not hinder colon tumor growth after PINK1 loss. To identify druggable targets in PINK1-deficient tumors, ribonucleic acid sequencing analysis was performed on colon tumors from pink1 knockout and wild-type mice. Gene Set Enrichment Analysis highlighted the enrichment of iron ion transmembrane transporter activity. Subsequent qualitative polymerase chain reaction and western blot analysis revealed an increase in mitochondrial iron transporters, including mitochondrial calcium uniporter, in PINK1-deficient colon tumor cells and tissues. Live-cell iron staining demonstrated elevated cellular and mitochondrial iron levels in PINK1-deficient cells. Clinically used drugs deferiprone and minocycline reduced mitochondrial iron and superoxide levels, resulting in decreased colon tumor cell growth in vitro and in vivo. Manipulating the mitochondrial iron uptake protein MCU (mitochondrial calcium uniporter) also affected cell and xenograft tumor growth. This study suggests that therapies aimed at reducing mitochondrial iron levels may effectively inhibit colon tumor growth, particularly in patients with low PINK1 expression.

Therapeutic targeting of the protein tyrosine kinase-7 in cancer: an overview.

The protein tyrosine kinase-7 (PTK7) is an evolutionarily conserved transmembrane receptor that has emerged as a potential therapeutic target for human tumors. PTK7 is a pseudokinase that is involved in the modulation of the Wnt signaling pathway through interactions with other receptors. These interactions result in targeted gene activation that regulates cell polarity, migration, and proliferation during embryogenesis. Aside of this role during development, PTK7 has been shown as overexpressed in numerous cancers including colon carcinoma, leukemia, neuroblastoma, hepatoma, and ovarian cancer. The activity of PTK7 and the direct correlation with poor prognosis have fostered preclinical investigations and phase I clinical trials, aiming at inhibiting PTK7 and inducing antitumoral effects. In this review, we provide an exhaustive overview of the diverse approaches that use PTK7 as a new molecular target for cancer therapy in different tumor types. We discuss current therapies and future strategies including chimeric antigen receptor-T cells, antibody-drug conjugates, aptamers, based on up-to-date literature and ongoing research progress.

Targeted nanoliposomes of oncogenic protein degraders: Significant inhibition of tumor in lung-cancer bearing mice

With 60 % of non-small cell lung cancer (NSCLC) expressing epidermal growth factor receptor (EGFR), it has been explored as an important therapeutic target for lung tumors. However, even the well-established EGFR inhibitors tend to promptly develop resistance over time. Moreover, strategies that could impede resistance development and be advantageous for both EGFR-Tyrosine kinase inhibitor (TKI)-sensitive and mutant NSCLC patients are constrained. Based on the critical relationship between EGFR, c-MYC, and Kirsten rat sarcoma virus (K-Ras), simultaneous degradation of EGFR and Bromodomain-containing protein 4 (BRD4) using “Proteolysis Targeting Chimeras (PROTACs)” could be a promising approach. PROTACs are emerging class of oncoprotein degraders but very challanging to deliver in vivo. Compared to individual IC50s, strong synergism was observed at 1:1 ratio of BPRO and EPRO in NSCLC cell lines with diverse mutation. Significant inhibition of cell growth with higher cellular apoptosis was observed in 2D and 3D-based cell assays in nanomolar concentrations. EGFR activation assay revealed 47.60 % EGFR non-expressing cells confirming EGFR-degrading potential of EPRO. A lung cancer specific nanoliposomal formulation of EGFR and BRD4-degrading PROTACs (EPRO and BPRO) was prepared and characetrized. Successful encapsulation of the two highly lipophilic molecules was achieved in EGFR-targeting nanoliposomal carriers (T-BEPRO) using a modified hydration technique. T-BEPRO revealed a particle size of 109.22 ± 0.266 nm with enhanced cellular uptake and activity. Remarkably, parenterally delivered T-BEPRO in tumor-bearing mice showed a substantially higher % tumor growth inhibition (TGI) of 77.6 % with long-lasting tumor inhibitory potential as opposed to individual drugs.

The DHODH inhibitor teriflunomide impedes cell proliferation and enhances chemosensitivity to daunorubicin (DNR) in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological tumor that requires novel treatment strategies, especially for relapsed/refractory cases. Dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway, has been identified as a potential target for tumors. Besides, Teriflunomide (TRF) is a DHODH inhibitor with anticancer effects; however, its role in T-ALL remains poorly understood. Here, we investigated the potential anticancer effects of TRF on T-ALL cells, and the results showed that TRF inhibited cell proliferation, caused S-phase cell cycle arrest, and promoted apoptosis of T-ALL (MOLT4 and JURKAT) cell lines. In addition, TRF reduced the infiltration capacity of T-ALL cells in T-ALL xenograft mice while up-regulating the expression of P53 and BTG2. The BTG2 knockdown significantly attenuated the inhibitory effect of TRF on cellular growth and suppressed the TRF-mediated elevated expression of P53 in T-ALL cells. Moreover, combined treatment with TRF and daunorubicin (DNR) significantly reduced cell viability and promoted apoptosis in DNR-resistant T-ALL cells. Our study provides valuable insights into the critical role of TRF in treating T-ALL while increasing the sensitivity of DNR-resistant T-ALL cells to DNR.

Solid cancer-directed CAR T cell therapy that attacks both tumor and immunosuppressive cells via targeting PD-L1

Chimeric antigen receptor (CAR) T-cell therapy has encountered limited success in solid tumors. The lack of dependable antigens and the immunosuppressive tumor microenvironment (TME) are major challenges. Within the TME, tumor cells along with immunosuppressive cells employ an immune-evasion mechanism that upregulates programmed death ligand 1 (PD-L1) to deactivate effector T cells; this makes PD-L1 a reliable, universal target for solid tumors. We developed a novel PD-L1 CAR (MC9999) using our humanized anti-PD-L1 monoclonal antibody, designed to simultaneously target tumor and immunosuppressive cells. The antigen-specific antitumor effects of MC9999 CAR T-cells were observed consistently across four solid tumor models: breast cancer, lung cancer, melanoma, and glioblastoma multiforme (GBM). Notably, intravenous administration of MC9999 CAR T-cells eradicated intracranially established LN229 GBM tumors, suggesting penetration of the blood-brain barrier. The proof-of-concept data demonstrate the cytolytic effect of MC9999 CAR T-cells against immunosuppressive cells, including microglia HMC3 cells and M2 macrophages. Furthermore, MC9999 CAR T-cells elicited cytotoxicity against primary tumor-associated macrophages within GBM tumors. The concept of targeting both tumor and immunosuppressive cells with MC9999 was further validated using CAR T-cells derived from cancer patients. These findings establish MC9999 as a foundation for the development of effective CAR T-cell therapies against solid tumors.

P2.14A.12 Unveiling COL17A1 as a Novel Cell Surface Target in Thymic Epithelial Tumors: A Target Discovery Pipeline Approach

P2.14A.12 Unveiling COL17A1 as a Novel Cell Surface Target in Thymic Epithelial Tumors: A Target Discovery Pipeline Approach

Relationship between adipocytes and hematological tumors in the bone marrow microenvironment: a literature review.

The bone marrow microenvironment is closely related to normal hematopoiesis and hematologic tumors. Adipocytes are an important part of the bone marrow microenvironment, in which they can release free fatty acids (FFAs) through lipolysis and secrete adipocytokines, etc., and participate in normal hematopoiesis, which is closely related to the occurrence and treatment of hematological tumors. In this review, we aim to discuss how bone marrow adipocytes (BMAs) can influence the proliferation, apoptosis, and chemotherapy resistance of cancer cells by reprogramming lipid metabolism and the secretion of various adipocytokines. Studies from 2000 to July 2024 were reviewed from PubMed, Springer Link, and the Web of Science using the keywords bone marrow microenvironment, adipocytes, lipid metabolism, adipocytokines, hematological tumor, cancer, and their combinations. Unreliable articles such as those that are old and have a low impact factor are excluded, and there is no restriction on language. Adipocytes can regulate the proliferation and differentiation of hematopoietic stem cells (HSCs) by secreting inflammatory factors and adipocytokines to maintain hematopoietic homeostasis. Adipocytes can also stimulate and accelerate the occurrence and progression of hematological tumors by secreting adipocytokines and mediating the reprogramming of lipid metabolism. Moreover, abundant adipocytes in bone marrow can protect tumor cells by physically blocking and/or secreting cytokines, leading to chemotherapy resistance. Therefore, the targeted inhibition of related lipid metabolism pathways and adipocytokines might be a potential therapeutic target for hematological tumors, which would be helpful to inhibit tumor growth and correct chemotherapy resistance.