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Novel therapeutic strategies targeting resistance mechanisms in hematologic malignancies: from BCL2 inhibition to immunomodulatory approaches.

BACKGROUND: Hematologic malignancies, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM), are characterized by high relapse rates due to intrinsic and acquired drug resistance. Resistance mechanisms often involve dysregulation of apoptosis pathways, such as B-cell lymphoma 2 (BCL2) family overexpression, and immune evasion through microenvironment modulation. PURPOSE: This review synthesizes recent advances (2020-2025) in therapeutic strategies targeting these mechanisms, focusing on BCL2 inhibition and immunomodul

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… This can result from irreversible genomic events (e.g., copy-neutral loss of heterozygosity leading to loss of an HLA haplotype) or from reversible epigenetic downregulation of HLA class II molecules and their regulator CIITA ( Chergui and Reagan, 2023 ). …

Malignant mesothelioma tumours: molecular pathogenesis, diagnosis, and therapies accompanying clinical studies.

The pathetic malignant mesothelioma (MM) is a extremely uncommon and confrontational tumor that evolves in the mesothelium layer of the pleural cavities (inner lining- visceral pleura and outer lining- parietal pleura), peritoneum, pericardium, and tunica vaginalis and is highly resistant to standard treatments. In mesothelioma, the predominant pattern of lesions is a loss of genes that limit tumour growth. Despite the worldwide ban on the manufacture and supply of asbestos, the prevalence of mesothelioma continues to increase. Mesothelioma presents and behaves in a variety of ways, making dia

Cancer Immunotherapy Beyond Checkpoint Blockade: JACC: CardioOncology State-of-the-Art Review.

Avoidance of immune destruction is recognized as one of the hallmarks of cancer development. Although first predicted as a potential antitumor treatment modality more than 50 years ago, the widespread clinical use of cancer immunotherapies has only recently become a reality. Cancer immunotherapy works by reactivation of a stalled pre-existing immune response or by eliciting a de novo immune response, and its toolkit comprises antibodies, vaccines, cytokines, and cell-based therapies. The treatment paradigm in some malignancies has completely changed over the past 10 to 15 years. Massive effort

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… However, the HLA restriction of neoantigens remains a potential limitation. 13 Additionally, HLA loss of heterozygosity in cancer cells is a known mechanism of immune escape, 21 occurring, for instance, in up to 40% of patients with non–small cell lung cancer (NSCLC), 22 and can prevent T cell recognition …

Molecular Classification and Overcoming Therapy Resistance for Acute Myeloid Leukemia with Adverse Genetic Factors.

The European LeukemiaNet (ELN) criteria define the adverse genetic factors of acute myeloid leukemia (AML). AML with adverse genetic factors uniformly shows resistance to standard chemotherapy and is associated with poor prognosis. Here, we focus on the biological background and real-world etiology of these adverse genetic factors and then describe a strategy to overcome the clinical disadvantages in terms of targeting pivotal molecular mechanisms. Different adverse genetic factors often rely on common pathways. KMT2A rearrangement, DEK-NUP214 fusion, and NPM1 mutation are associated with the

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… Mutations With Loss of Heterozygosity of P53 Are Common in Therapy-Related Myelodysplasia and Acute Myeloid Leukemia After Exposure to Alkylating Agents and Significantly Associated With Deletion or Loss of 5q, a Complex Karyotype, and a Poor Prognosis. …

Von Hippel-Lindau Disease: Current Challenges and Future Prospects.

Understanding of molecular mechanisms of tumor growth has an increasing impact on the development of diagnostics and targeted therapy of human neoplasia. In this review, we summarize the current knowledge on molecular mechanisms and their clinical implications in von Hippel-Lindau (VHL) disease. This autosomal dominant tumor syndrome usually manifests in young adulthood and predisposes affected patients to the development of benign and malignant tumors of different organ systems mainly including the nervous system and internal organs. A consequent screening and timely preventive treatment of l

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… Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas. Cancer Res . 1998;58(3):504–508. 32. Wizigmann-Voos S, Breier G, Risau W, Plate KH. …

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells.

Hematopoietic stem cells (HSCs) are a rare subset of bone marrow cells that usually exist in a quiescent state, only entering the cell cycle to replenish the blood compartment, thereby limiting the potential for errors in replication. Inflammatory signals that are released in response to environmental stressors, such as infection, trigger active cycling of HSCs. These inflammatory signals can also directly induce HSCs to release cytokines into the bone marrow environment, promoting myeloid differentiation. After stress myelopoiesis is triggered, HSCs require intracellular signaling programs to

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… Loss of heterozygosity of TIFAB causes bone marrow failure and significant changes in myeloid differentiation. Gene expression analysis in TIFAB knockout HSPCs revealed the upregulation of immune and infection response signatures, which suggests hypersensititivy to TLR4 stimulation. …

Exploring Affordable Curative Therapy for Sickle Cell Disease in Africa: A Comprehensive Overview.

The practical aspects of developing curative treatments for sickle cell disease (SCD) in Africa, such as gene therapy and hematopoietic stem cell transplantation, involve strengthening healthcare infrastructure, training healthcare professionals, establishing regional treatment centers, and creating national SCD programs. The costs associated with gene therapy and stem cell transplants can be prohibitive, especially in low- and middle-income countries. Strategies to address affordability, including local manufacturing, government funding, and partnerships with global health agencies, are essen

Defining neuroblastoma: From origin to precision medicine.

Neuroblastoma (NB), a heterogenous pediatric tumor of the sympathetic nervous system, is the most common and deadly extracranial solid malignancy diagnosed in infants. Numerous efforts have been invested in understanding its origin and in development of novel curative targeted therapies. Here, we summarize the recent advances in the identification of the cell of origin and the genetic alterations occurring during development that contribute to NB. We discuss current treatment regimens, present and future directions for the identification of novel therapeutic metabolic targets, differentiation

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… Loss of heterozygosity at 1p36 independently predicts for disease progression but not decreased overall survival probability in neuroblastoma patients: a children’s cancer group study. J Clin Oncol. 2000;18(9):1888–1899. 26. Bown N, Cotterill S, Lastowska M, et al. …

Резюме докладов 53rd Конференция Европейского общества генетики человека: интерактивные электронные постеры.

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Prognostic pan-cancer and single-cancer models: A large-scale analysis using a real-world clinico-genomic database.

Prognostic models in oncology have a profound impact on personalized cancer care and patient profiling, but tend to be heterogeneously developed and implemented in narrow patient cohorts. Here, we develop and benchmark multiple machine learning models to predict survival in pan-cancer and 16 single-cancer settings using a de-identified clinico-genomic database of 28,079 US patients with cancer. We identify key predictors of cancer prognosis, including 15 shared across seven or more cancer types, revealing strong consistency in cancer prognostic factors. We demonstrate that pan-cancer models ge

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… While the majority of specimen-derived features harnessed the Foundation Medicine mutation readout, a handful of standalone scores were also incorporated – tumor mutational burden, tumor purity, PDL1 status, estimated percentage of genome loss of heterozygosity, and microsatellite instability status. …

Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease.

The treatment landscape of acute myeloid leukaemia (AML) is evolving rapidly. Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials. The development of mutation-targeted therapies has greatly enhanced the treatment armamentarium, with FLT3 inhibitors and isocitrate dehydrogenase inhibitors improving outcomes in frontline and relapsed/refractory (RR) AML, and menin inhibitors showing efficacy in RR NPM1mut and KMT2A-rearranged AML. With so many new drugs approved, the number of potential combinator

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… Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis . …

Familial Cerebral Cavernous Malformations: Pathophysiology, Genetics, Biomarkers, and Treatment Perspectives.

Familial cerebral cavernous malformations (FCCM) are a heritable neurovascular disorder defined by clusters of dilated, thin-walled capillaries in the brain and spinal cord. Although rare, FCCM offers a tractable model for understanding how genetic disruptions in endothelial junction biology, mechanotransduction, and kinase signaling drive vascular instability in the central nervous system. Pathogenic loss-of-function variants converge on signaling abnormalities that promote barrier dysfunction, iron deposition, inflammation, and progressive lesional growth. Clinically, FCCM may manifest with

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… In vivo, loss of heterozygosity for either CCM3/ PDCD10 or GCKIII produces vessels with narrowed or irregular lumina, accompanied by dilation of adjacent microvascular segments, strikingly reminiscent of the cavernous, thin‐walled architecture characteristic of CCM lesions (Chan et al. 2011 ). …

Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention.

The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2, ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstre

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… The presence of loss of heterozygosity (LOH) at the CHK2 gene was examined in 139 breast cancer tumors [ 68 ]. 139 breast tumors were screened for loss of heterozygosity (LOH) at chromosome 22q (where the CHK2 gene is located), using seven microsatellite markers, LOH was detected in 53% of the breast …

Lysosomal storage diseases.

Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage ca

Cell-based immunotherapy of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary glial brain tumor. It has an unfavorable prognosis and relatively ineffective treatment protocols, with the median survival of patients being ~15 months. Tumor resistance to treatment is associated with its cancer stem cells (CSCs). At present, there is no medication or technologies that have the ability to completely eradicate CSCs, and immunotherapy (IT) is only able to prolong the patient's life. The present review aimed to investigate systemic solutions for issues associated with immunosuppression, such as ineffective

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… Treatment resistance factors At the genomic level ( 26 ), treatment resistance is caused by a unique range of genetic mutations, including the loss of heterozygosity on human chromosome 10q, the homozygous deletion of p16INK4a and mutations in Rb and TP53 genes, cyclin-dependent kinases and the tyrosine …

Epigenetic Therapies for Acute Myeloid Leukemia and Their Immune-Related Effects.

Over the past decades, our molecular understanding of acute myeloid leukemia (AML) pathogenesis dramatically increased, thanks also to the advent of next-generation sequencing (NGS) technologies. Many of these findings, however, have not yet translated into new prognostic markers or rationales for treatments. We now know that AML is a highly heterogeneous disease characterized by a very low mutational burden. Interestingly, the few mutations identified mainly reside in epigenetic regulators, which shape and define leukemic cell identity. In the light of these discoveries and given the increasi

An update on malignant tumor-related stiff person syndrome spectrum disorders: clinical mechanism, treatment, and outcomes.

Stiff person syndrome (SPS) is a rare central nervous system disorder associated with malignancies. In this review, we retrieved information from PubMed, up until August 2023, using various search terms and their combinations, including SPS, stiff person syndrome spectrum disorders (SPSSDs), paraneoplastic, cancer, and malignant tumor. Data from peer-reviewed journals printed in English were organized to explain the possible relationships between different carcinomas and SPSSD subtypes, as well as related autoantigens. From literature searching, it was revealed that breast cancer was the most

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… Loss of heterozygosity and tumor suppressor activity of Bin1 in prostate carcinoma. Int J Cancer. (2000) 86:155–61. 10.1002/(sici)1097-0215(20000415)86:2<155::aid-ijc2>3.0.co;2-m 151. Ge K, DuHadaway J, Du W, Herlyn M, Rodeck U, Prendergast GC. …

Proteasome Inhibitors and Their Potential Applicability in Osteosarcoma Treatment.

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

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… Studies comparing primary OS tumors to their paired metastases using whole exome sequencing and phylogenetic analysis found ubiquitous loss of heterozygosity in chromosome region 17p (harboring TP53) in primary and secondary tumors, suggesting that loss of p53 is an early event during OS progression …

The Proliferative and Apoptotic Landscape of Basal-like Breast Cancer.

Basal-like breast cancer (BLBC) is an aggressive molecular subtype that represents up to 15% of breast cancers. It occurs in younger patients, and typically shows rapid development of locoregional and distant metastasis, resulting in a relatively high mortality rate. Its defining features are that it is positive for basal cytokeratins and, epidermal growth factor receptor and/or c-Kit. Problematically, it is typically negative for the estrogen receptor and human epidermal growth factor receptor 2 (HER2), which means that it is unsuitable for either hormone therapy or targeted HER2 therapy. As

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… RB loss is prevalent across all ER- tumors [ 50 , 51 ] and is particularly high in BLBC, where up to 76% of tumors show loss of heterozygosity (LOH) of the RB1 gene encoding RB [ 52 ]. …

Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies.

Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment str

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… ERMS is associated with a loss of heterozygosity at the 11p15 locus in 80% of the cases, which results in an altered insulin-like growth factor 2 (IGF2) gene [ 3 , 23 ]. … of heterozygosity at 11p15 (IGF-2 gene) [ 3 ]; associated with familial cancer syndromes, e.g., LFS, NF1 | 60% are t(2:13)(q35:114): PAX3-FOXO1 positive [ 3 ]; 20% are t(1;13)(p36;q14): PAX7-FOXO1 positive [ 1 ]; 20% are FN; resemble ERMS characteristics/prognosis [ 3 ] | NA | NA Histology | Immature …