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Targeted therapy in the treatment of malignant gliomas.

Malignant gliomas are invasive tumors with the potential to progress through current available therapies. These tumors are characterized by a number of abnormalities in molecular signaling that play roles in tumorigenesis, spread, and survival. These pathways are being actively investigated in both the pre-clinical and clinical settings as potential targets in the treatment of malignant gliomas. We will review many of the therapies that target the cancer cell, including the epidermal growth factor receptor, mammalian target of rapamycin, histone deacetylase, and farnesyl transferase. In additi

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… Loss of heterozygosity (LOH) for either the TSC1 or TSC2 locus was found in less than 10% of grade III and IV astrocytomas. No mutations of the intact allele were found. It is possible that LOH at these loci is merely an expression of the myriad genetic aberrancies in malignant gliomas. …

CAR-T cell therapy: developments, challenges and expanded applications from cancer to autoimmunity.

Chimeric Antigen Receptor (CAR)-T cell therapy has rapidly emerged as a groundbreaking approach in cancer treatment, particularly for hematologic malignancies. However, the application of CAR-T cell therapy in solid tumors remains challenging. This review summarized the development of CAR-T technologies, emphasized the challenges and solutions in CAR-T cell therapy for solid tumors. Also, key innovations were discussed including specialized CAR-T, combination therapies and the novel use of CAR-Treg, CAR-NK and CAR-M cells. Besides, CAR-based cell therapy have extended its reach beyond oncology

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… Neoplasm-targeting allele-sensing CAR (NASCAR), is designed to target a mutation commonly found in the cancer transformation process called clonal loss of heterozygosity (LOH). …

Perspectives on the Risk-Stratified Treatment of Multiple Myeloma.

The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article d

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… Appropriate panel design can also enable detection of copy-number abnormalities, regions of loss of heterozygosity (LOH), and copy-number neutral LOH. …

Effective Immunosurveillance After Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia.

The number of patients receiving allogeneic hematopoietic stem cell transplantation (alloHCT) has increased constantly over the last years due to advances in transplant technology development, supportive care, transplant safety, and donor availability. Currently, acute myeloid leukemia (AML) is the most frequent indication for alloHCT. However, disease relapse remains the main cause of therapy failure. Therefore, concepts of maintaining and, if necessary, reinforcing a strong graft-versus-leukemia (GvL) effect is crucial for the prognosis and long-term survival of the patients. Over the last d

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… In 2009, Vago et al demonstrated an acquired uniparental disomy (aUPD) of chromosome 6p by copy-neutral loss of heterozygosity in the HLA locus (HLA loss) after haploHCT in one-third of relapsed cases. 135 For the MMUD setting, HLA loss is observed in about 5–25% of cases; after MUD transplantation, …

Therapeutic approaches in myelofibrosis and myelodysplastic/myeloproliferative overlap syndromes.

The discovery of JAK2 (V617F) a decade ago led to optimism for a rapidly developing treatment revolution in Ph(-) myeloproliferative neoplasms. Unlike BCR-ABL, however, JAK2 was found to have a more heterogeneous role in carcinogenesis. Therefore, for years, development of new therapies was slow, despite standard treatment options that did not address the overwhelming symptom burden in patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, post-polycythemia vera MF, and myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) syndromes. JAK-STAT inhibitors have ch

Kinase Inhibitors and Ovarian Cancer.

Ovarian cancer is fifth in the rankings of cancer deaths among women, and accounts for more deaths than any other gynecological malignancy. Despite some improvement in overall-(OS) and progression-free survival (PFS) following surgery and first-line chemotherapy, there is a need for development of novel and more effective therapeutic strategies. In this mini review, we provide a summary of the current landscape of the clinical use of tyrosine kinase inhibitors (TKIs) and mechanistic target of rapamycin (mTOR) inhibitors in ovarian cancer. Emerging data from phase I and II trials reveals that a

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… “Contextual” synthetic lethality and/or loss of heterozygosity: Tumor hypoxia and modification of DNA repair. Clin. Cancer Res. 2010;16:4553–4560. doi: 10.1158/1078-0432.CCR-10-0527. 51. Hegan D.C., Lu Y., Stachelek G.C., Crosby M.E., Bindra R.S., Glazer P.M. …

Emerging treatment options for patients with p53-pathway-deficient CLL.

Over the past 40 years, p53 has been the most widely studied protein in cancer biology. Originally thought to be an oncogene due to its stabilization in many cancers, it is now considered to be one of the most critical tumor suppressors in a cell's ability to combat neoplastic transformation. Due to its critical roles in apoptosis, cell-cycle arrest, and senescence, TP53 deletions and mutations are commonly observed and are often a portent of treatment failures and poor clinical outcomes. This is particularly true in chronic lymphocytic leukemia (CLL), as patients with p53 alterations have his

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… Indeed, almost 80% of cases with del(17p) will harbor a TP53 mutation in the remaining allele, a phenomenon referred to as loss of heterozygosity (LOH). 12 Importantly, mutations in TP53 have also been observed in the absence of 17p deletions and have been associated with poor prognosis, even in this …

Safety and Tolerability of Letetresgene Autoleucel (GSK3377794): Pilot Studies in Patients with Advanced Non-Small Cell Lung Cancer.

PurposeThe study aims to evaluate the safety, tolerability, and antitumor response of letetresgene autoleucel (lete-cel), genetically modified autologous T cells expressing a T-cell receptor specific for New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in HLA-A*02-positive (HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06) patients with NY-ESO-1- and/or LAGE-1a-positive non-small cell lung cancer.Patients and methodsStudy 208749 was a single-arm study of lete-cel alone. Study 208471 was a multiarm study of lete-cel alone o

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… Screening for HLA loss of heterozygosity refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens ( 51 ). …

Therapeutic Targeting of DNA Damage Repair in the Era of Precision Oncology and Immune Checkpoint Inhibitors.

Cancer manifestation is a multistep process involving accumulation of various genetic and epigenetic changes that results in oncogenic "hallmarks of cancer" processes including genomic instability. Exploitation of aberrant DNA-damage response (DDR) mechanisms in cancer is in part a goal of many therapeutic strategies, and recent evidence supports the role of targeting DDR in modulating the tumor immune microenvironment to enhance immunotherapeutic response. Improved cancer profiling, including next-generation and whole-genome mutational sequencing of tumor tissue, as well as circulating nuclei

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… Apart from BRCA1/2 mutations, biomarkers that predict response to PARPi in ovarian cancer include RAD51C and RAD51D mutations, presence of HRD [as defined by high degree of locus-specific loss of heterozygosity (LOH)], and high-level BRCA1 promoter methylation.[ 37 ] PARPi monotherapy also has demonstrated …

Targeting translation initiation in breast cancer.

Over the past 20 years, a better understanding of cancer biology, screening for early detection, improved adjuvant treatment, and targeted therapies have decreased the rate of breast cancer deaths. However, resistance to treatment is common, and new approaches are needed. Deregulation of translation initiation is associated with the commencement and progression of cancer. Often, translation initiation factors are overexpressed and the related signaling pathways activated in human tumors. Recently, a significant number of inhibitors that target translation factors and pathways have become avail

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… Increased expression of truncated eIF3e induces malignant transformation of normal mammary cells in vitro. 39 The EIF3E gene was found to have reduced expression in 37% and loss of heterozygosity in 21% of human breast cancers, implicating a loss of EIF3 activity in the development and progression of …

The Challenging Approach to Multiple Myeloma: From Disease Diagnosis and Monitoring to Complications Management.

The outcome of multiple myeloma (MM) has significantly improved in the last few decades due to several factors such as new biological discoveries allowing to better stratify disease risk, development of more effective therapies and better management of side effects related to them. However, handling all these aspects requires an interdisciplinary approach involving multiple knowledge and collaboration of different specialists. The hematologist, faced with a patient with MM, must not only choose a treatment according to patient and disease characteristics but must also know when therapy needs t

Autoinflammatory Keratinization Diseases-The Concept, Pathophysiology, and Clinical Implications.

Recent advances in medical genetics elucidated the background of diseases characterized by superficial dermal and epidermal inflammation with resultant aberrant keratosis. This led to introducing the term autoinflammatory keratinization diseases encompassing entities in which monogenic mutations cause spontaneous activation of the innate immunity and subsequent disruption of the keratinization process. Originally, autoinflammatory keratinization diseases were attributed to pathogenic variants of CARD14 (generalized pustular psoriasis with concomitant psoriasis vulgaris, palmoplantar pustulosis

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… Porokeratosis (OMIM nos. 175900; 175800; 614714; 616631) is an autosomal dominant disorder developing as a result of second-hit somatic mutation causing loss of heterozygosity [ 160 ]. …

Strategies to Improve Sensitivity to Radiotherapy in Pediatric Solid Tumors.

The primary goal in the treatment of pediatric malignancies is to maintain effective cancer control while minimizing toxicities and late effects. Radiotherapy is a component of standard therapy against many pediatric cancers, but tumor cell DNA damage repair mechanisms and the hypoxic tumor microenvironment may limit the effectiveness of this modality. Additionally, irradiated cancer cells often acquire resistance to radiotherapy that permits cancer cell survival or stimulates tumor regrowth after treatment, further limiting the efficacy of radiotherapy. Various preclinical studies have invest

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… Augmentation of Therapy for Combined Loss of Heterozygosity 1p and 16q in Favorable Histology Wilms Tumor: A Children’s Oncology Group AREN0532 and AREN0533 Study Report. J. Clin. Oncol. 2019;37:2769–2777. doi: 10.1200/JCO.18.01972. 106. …

The Role of DNA Repair in Genomic Instability of Multiple Myeloma.

Multiple Myeloma (MM) is a B cell malignancy marked by genomic instability that arises both through pathogenesis and during disease progression. Despite recent advances in therapy, MM remains incurable. Recently, it has been reported that DNA repair can influence genomic changes and drug resistance in MM. The dysregulation of DNA repair function may provide an alternative explanation for genomic instability observed in MM cells and in cells derived from MM patients. This review provides an overview of DNA repair pathways with a special focus on their involvement in MM and discusses the role th

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… Loss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: A role for PARP inhibition? Leukemia 2018 32 1561 1566 10.1038/s41375-018-0017-0 29467487 PMC6035152 30. Walker B.A. Boyle E.M. Wardell C.P. Murison A. Begum D.B. Dahir N.B. Proszek P.Z. Johnson D.C. …

Polymorphisms of Antigen-Presenting Machinery Genes in Non-Small Cell Lung Cancer: Different Impact on Disease Risk and Clinical Parameters in Smokers and Never-Smokers.

Lung cancer is strongly associated with cigarette smoking; nevertheless some never-smokers develop cancer. Immune eradication of cancer cells is dependent on polymorphisms of HLA class I molecules and antigen-processing machinery (APM) components. We have already published highly significant associations of single nucleotide polymorphisms (SNPs) of the ERAP1 gene with non-small cell lung cancer (NSCLC) in Chinese, but not in Polish populations. However, the smoking status of participants was not known in the previous study. Here, we compared the distribution of APM polymorphic variants in larg

Molecular therapeutic approaches for pediatric acute myeloid leukemia.

Approximately two-thirds of children with acute myeloid leukemia (AML) are cured with intensive multi-agent chemotherapy. However, refractory and relapsed AML remains a significant source of childhood cancer mortality, highlighting the need for new therapies. Further therapy intensification with traditional cytotoxic chemotherapy in pediatric AML is not feasible given the risks of both short-term and long-term organ dysfunction. Substantial emphasis has been placed upon the development of molecularly targeted therapeutic approaches for adults and children with high-risk subtypes of AML with th

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… Identification of novel somatic mutations, regions of recurrent loss of heterozygosity (LOH) and significant clonal evolution from diagnosis to relapse in childhood AML determined by exome capture sequencing – an NCI/COG target AML study. Blood (2012) 120(21):123 …

Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials.

Chemotherapy is one of the most established and effective treatments for almost all types of cancer. However, the elevated toxicity due to the non-tumor-associated effects, development of secondary malignancies, infertility, radiation-induced fibrosis and resistance to treatment limit the effectiveness and safety of treatment. In addition, these multiple factors significantly impact quality of life. Over the last decades, our increased understanding of cancer epigenetics has led to new therapeutic approaches and the promise of improved patient outcomes. Epigenetic alterations are commonly foun

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… Genome-wide loss of heterozygosity and copy number analysis in melanoma using high-density single-nucleotide polymorphism arrays. Cancer Res. 67 2632–2642. 10.1158/0008-5472.can-06-4152 Suraweera A., O’byrne K. J., Richard D. J. (2018). …

The "Road" to Malignant Transformation from Endometriosis to Endometriosis-Associated Ovarian Cancers (EAOCs): An mTOR-Centred Review.

Ovarian cancer is an umbrella term covering a number of distinct subtypes. Endometrioid and clear-cell ovarian carcinoma are endometriosis-associated ovarian cancers (EAOCs) frequently arising from ectopic endometrium in the ovary. The mechanistic target of rapamycin (mTOR) is a crucial regulator of cellular homeostasis and is dysregulated in both endometriosis and endometriosis-associated ovarian cancer, potentially favouring carcinogenesis across a spectrum from benign disease with cancer-like characteristics, through an atypical phase, to frank malignancy. In this review, we focus on mTOR d

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… Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: Possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res. 2000;60:7052–7056. 114. …

Mechanistic and Clinical Perspectives on Traditional Chinese Medicine in Thyroid Cancer Management.

Thyroid cancer is one of the most prevalent malignancies of the endocrine system, comprising various subtypes such as papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), and the aggressive anaplastic thyroid carcinoma (ATC). Despite a generally favorable prognosis for PTC, recurrence, metastasis, and resistance to conventional therapies continue to pose significant challenges. The pathogenesis of thyroid cancer involves genetic mutations in BRAF, RAS, and RET, as well as dysregulated molecular pathways such as MAPK, PI3K/Akt/mTOR, and NF-κB

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… The mechanisms that cause PTEN inactivation include mutations, loss of heterozygosity, deletions, and epigenetic alterations that lead to PTEN downregulation. …

Combining germline, tissue and liquid biopsy analysis by comprehensive genomic profiling to improve the yield of actionable variants in a real-world cancer cohort.

BACKGROUND: Comprehensive next-generation sequencing is widely used for precision oncology and precision prevention approaches. We aimed to determine the yield of actionable gene variants, the capacity to uncover hereditary predisposition and liquid biopsy appropriateness instead of, or in addition to, tumor tissue analysis, in a real-world cohort of cancer patients, who may benefit the most from comprehensive genomic profiling. METHODS: Seventy-eight matched germline/tumor tissue/liquid biopsy DNA and RNA samples were profiled using the Hereditary Cancer Panel (germline) and the TruSight Onc

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… Pastorino L Dalmasso B Allavena E Vanni I Ugolini F Baroni G Ataxia-telangiectasia mutated loss of heterozygosity in melanoma Int J Mol Sci 2022 23 24 16027 10.3390/ijms232416027 36555667 PMC9786167 52. …