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CXD101 and nivolumab in patients with metastatic microsatellite-stable colorectal cancer (CAROSELL): a multicentre, open-label, single-arm, phase II trial.

BackgroundPatients with microsatellite stable (MSS) colorectal carcinoma (CRC) do not respond to immune checkpoint inhibitors. Preclinical models suggested synergistic anti-tumour activity combining CXD101 and anti-programmed cell death protein 1 treatment; therefore, we assessed the clinical combination of CXD101 and nivolumab in heavily pre-treated patients with MSS metastatic CRC (mCRC).Patients and methodsThis single-arm, open-label study enrolled patients aged 18 years or older with biopsy-confirmed MSS CRC; at least two lines of systemic anticancer therapies (including oxaliplatin and ir

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… DNA mismatch repair deficiency (dMMR) causes slippage at DNA microsatellites—referred to as microsatellite instability (MSI)—and accumulation of mutations, resulting in increased neoantigen load and tumour recognition by infiltrating lymphocytes. 5 The categorisation of CRC into MSS and MSI is highly … Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182–1191. doi: 10.1016/S1470-2045(17)30422-9. 7. Le D.T., Uram J.N., Wang H., et al. …

Targeted Therapies in Advanced Cholangiocarcinoma.

Primary tumor resection and liver transplantation are the only curative treatment options for the management of cholangiocarcinoma (CCA). However, for patients with advanced or metastatic disease, palliative systemic therapy remains the only treatment option. The development of targeted therapeutics has begun to shift the treatment paradigm in CCA. Targets of interest in CCA include mutated isocitrate dehydrogenase-1 (mIDH-1), human epidermal growth factor receptor 2 (HER2) overexpression/amplification, and fibroblast growth factor receptor 2 (FGFR2) fusion, in addition to less frequently obse

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… DNA Mismatch Repair Proteins: Scientific Update and Practical Guide. J. Clin. Pathol. 2021;74:264–268. doi: 10.1136/jclinpath-2020-207281. 80. Olave M.C., Graham R.P. Mismatch Repair Deficiency: The What, How and Why It Is Important. Genes. … Clinical and Genetic Implications of DNA Mismatch Repair Deficiency in Biliary Tract Cancers Associated with Lynch Syndrome. J. Gastrointest. Cancer. 2018;49:93–96. doi: 10.1007/s12029-017-0040-9. 86. …

CRISPR-Cas: Converting A Bacterial Defence Mechanism into A State-of-the-Art Genetic Manipulation Tool.

Bacteriophages are pervasive viruses that infect bacteria, relying on their genetic machinery to replicate. In order to protect themselves from this kind of invader, bacteria developed an ingenious adaptive defence system, clustered regularly interspaced short palindromic repeats (CRISPR). Researchers soon realised that a specific type of CRISPR system, CRISPR-Cas9, could be modified into a simple and efficient genetic engineering technology, with several improvements over currently used systems. This discovery set in motion a revolution in genetics, with new and improved CRISPR systems being

Targeting the DNA Damage Response for Cancer Therapy.

Over the course of long-term evolution, cells have developed intricate defense mechanisms in response to DNA damage; these mechanisms play a pivotal role in maintaining genomic stability. Defects in the DNA damage response pathways can give rise to various diseases, including cancer. The DNA damage response (DDR) system is instrumental in safeguarding genomic stability. The accumulation of DNA damage and the weakening of DDR function both promote the initiation and progression of tumors. Simultaneously, they offer opportunities and targets for cancer therapeutics. This article primarily elucid

A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance.

A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating agent temozolomide (TMZ), which was approved by the FDA in 2005 based on a marginal increase (~2 months) in overall survival (OS) levels. This treatment approach, while initially successful in containing and treating GBM, almost invariably fails to prevent tumor recurrence. In addition to

Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment.

Platinum-based chemotherapies, such as cisplatin, play a large role in cancer treatment. The development of resistance and treatment toxicity creates substantial barriers to disease control, yet. To enhance the therapeutic index of cisplatin-based chemotherapy, it is imperative to circumvent resistance and toxicity while optimizing tumor sensitization. One of the primary mechanisms by which cancer cells develop resistance to cisplatin is through upregulation of DNA repair pathways. In this review, we discuss the DNA damage response in the context of cisplatin-induced DNA damage. We describe th

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… The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα Cell 2013 153 590 600 10.1016/j.cell.2013.03.025 23622243 PMC3641580 72. Li G.M. … Loss of DNA mismatch repair due to knockout of MSH2 or PMS2 results in resistance to cisplatin and carboplatin Int. J. Oncol. 1997 11 539 542 10.3892/ijo.11.3.539 21528244 74. Takahashi M. Koi M. Balaguer F. Boland C.R. Goel A. …

Redefining the battle against colorectal cancer: a comprehensive review of emerging immunotherapies and their clinical efficacy.

Colorectal cancer (CRC) is the third most common cancer globally and presents a significant challenge owing to its high mortality rate and the limitations of traditional treatment options such as surgery, radiotherapy, and chemotherapy. While these treatments are foundational, they are often poorly effective owing to tumor resistance. Immunotherapy is a groundbreaking alternative that has recently emerged and offers new hope for success by exploiting the body's own immune system. This article aims to provide an extensive review of clinical trials evaluating the efficacy of various immunotherap

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

Immunotherapy for pediatric solid tumors: overcoming biological barriers through rational multimodal combinations.

Pediatric solid tumors remain among the most treatment-refractory childhood malignancies, defined by biological features that have largely resisted the immunotherapeutic advances transforming adult oncology. Exceptionally low tumor mutational burden, sparse neoantigen landscapes, and profoundly immunosuppressive tumor microenvironments collectively undermine the T cell-dependent mechanisms on which most current immunotherapies depend. Yet the field is undergoing a meaningful shift. Anti-GD2 monoclonal antibodies have established a survival benchmark in high-risk neuroblastoma, and next-generat

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… Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency in children harbor the highest mutational and microsatellite insertion–deletion burden in humans, and treatment with ICIs in an international consortium registry study of 38 patients demonstrated durable … He Y, Zhang L, Zhou R, Wang Y, Chen H (2022) The role of DNA mismatch repair in immunotherapy of human cancer. Int J Biol Sci. 18(7):2821 103. …

Molecular Targeting and Rational Chemotherapy in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a molecularly complex disease with multiple aberrant genetic pathways involved in its pathogenesis. Approximately one-third to one-half of patients with AML would relapse, and no standard therapy is established for relapsing and/or refractory AML (RR-AML) yet. It is unlikely that blockage of only one specific pathway will lead to prolonged remissions and cures in all fractions of the AML patients population. Nowadays, novel therapeutic agents with rational combination are being recognized which improve the cure rate for relapsed AML. These drugs and their metabo

Mitochondrial Genetic and Epigenetic Regulations in Cancer: Therapeutic Potential.

Mitochondria are dynamic organelles managing crucial processes of cellular metabolism and bioenergetics. Enabling rapid cellular adaptation to altered endogenous and exogenous environments, mitochondria play an important role in many pathophysiological states, including cancer. Being under the control of mitochondrial and nuclear DNA (mtDNA and nDNA), mitochondria adjust their activity and biogenesis to cell demands. In cancer, numerous mutations in mtDNA have been detected, which do not inactivate mitochondrial functions but rather alter energy metabolism to support cancer cell growth. Increa

Modern therapeutic approaches in cholangiocarcinoma: A narrative review of key biomarkers and clinical trials.

Cholangiocarcinoma (CCA), the second most common hepatic malignancy after hepatocellular carcinoma, presents a significant clinical challenge. This epithelial cell malignancy occurs in various anatomical subtypes, including intrahepatic, perihilar, and distal, each associated with unique genetic aberrations, clinical presentations, and treatment options. Early diagnosis is challenging, leading to poor survival rates, especially in advanced cases. Precision medicine offers hope for improved management of CCA by tailoring treatments based on molecular profiling. In recent years, the investigatio

Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review.

Upon the induction of DNA damage, the chromatin structure unwinds to allow access to enzymes to catalyse the repair. The regulation of the winding and unwinding of chromatin occurs via epigenetic modifications, which can alter gene expression without changing the DNA sequence. Epigenetic mechanisms such as histone acetylation and DNA methylation are known to be reversible and have been indicated to play different roles in the repair of DNA. More importantly, the inhibition of such mechanisms has been reported to play a role in the repair of double strand breaks, the most detrimental type of DN

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… DNA Mismatch Repair. Annu. Rev. Biochem. 74 (1), 681–710. 10.1146/annurev.biochem.74.082803.133243 Lakshmaiah K. C., Jacob L. A., Aparna S., Lokanatha D., Saldanha Smitha. C. (2014). Epigenetic Therapy of Cancer with Histone Deacetylase Inhibitors. J. Cancer Res. …

Hypercalcemia in poorly differentiated endometrial cancer: a report of two cases.

BACKGROUND: Hypercalcemia as a paraneoplastic syndrome is associated with poor prognosis. It is most commonly caused by parathyroid hormone-related protein (PTHrP) production, less commonly by bony metastases, and very rarely by ectopic parathyroid hormone (PTH) secretion. Hypercalcemia in endometrial cancer is relatively rare. CASE PRESENTATION: We present two cases of hypercalcemia in patients with poorly differentiated endometrial cancer, both of whom had elevated PTH levels and no evidence of parathyroid disease or bone metastases at baseline. In the first case, hypercalcemia rapidly prog

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… Case Pathology Site Calcium, Highest (mg/dL), NR: 8.5–10.5 PTH, Highest (pg/mL), NR: 24–85 Tumor DNA mismatch repair status Treatment Survival Case 1 FIGO G3 (poorly differentiated) carcinoma Endometrial 16.2 167 Deficient in MLH1 and PMS2 TAH-BSO 1 month after initial presentation Case 2 FIGO grade … Case | Pathology | Site | Calcium, Highest (mg/dL), NR: 8.5–10.5 | PTH, Highest (pg/mL), NR: 24–85 | Tumor DNA mismatch repair status | Treatment | Survival Case 1 | FIGO G3 (poorly differentiated) carcinoma | Endometrial | 16.2 | 167 | Deficient in MLH1 and PMS2 | TAH-BSO | 1 month after initial presentation …

Innovation in Oncology Drug Development.

Significant progress has been made in our understanding of the molecular lesions responsible for tumor cells to exhibit uncontrolled growth while circumventing normal mechanisms of apoptosis and their ability to migrate and invade normal tissues while evading recognition and destruction by the immune system. This understanding has enabled the development of therapies specifically targeted to these lesions coupled to innovative treatment regimens to most effectively use these new targeted therapies with precision in selected subpopulations of patients. Innovation at the scientific and clinical

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… Defective DNA mismatch repair in long-term (≥3 years) survivors with pancreatic cancer. Pancreatology. 2005;5(2-3):220–228. doi: 10.1159/000085275. 49. Meltzer S. J., Yin J., Manin B, et al. … DNA mismatch repair deficiency in ampullary carcinoma. American Journal of Clinical Pathology. 2010;133(5):772–780. doi: 10.1309/ajcpgdde8plldrcc. 52. Garg K., Leitao M. M., Kauff N. D., et al. …

Comprehensive understanding of the adverse effects associated with temozolomide: a disproportionate analysis based on the FAERS database.

BACKGROUND: Temozolomide, which is the standard drug for glioma treatment, has several Adverse events (AEs) in the treatment of gliomas and other tumors that are not yet fully understood. This is due to the pharmacological nature of the alkylating agent. A significant proportion of these effects have not been systematically documented or reported. METHODS: We selected data from the United States FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the fourth quarter of 2023. Four algorithms were used for disproportionate analysis, with the objective of assessi

Targeting homologous recombination and telomerase in Barrett's adenocarcinoma: impact on telomere maintenance, genomic instability and tumor growth.

Homologous recombination (HR), a mechanism to accurately repair DNA in normal cells, is deregulated in cancer. Elevated/deregulated HR is implicated in genomic instability and telomere maintenance, which are critical lifelines of cancer cells. We have previously shown that HR activity is elevated and significantly contributes to genomic instability in Barrett's esophageal adenocarcinoma (BAC). The purpose of this study was to evaluate therapeutic potential of HR inhibition, alone and in combination with telomerase inhibition, in BAC. We demonstrate that telomerase inhibition in BAC cells incre

Influence of Hypoxia on Tumor Heterogeneity, DNA Repair, and Cancer Therapy: From Molecular Insights to Therapeutic Strategies.

Hypoxia, characterized by a reduction in tissue oxygen levels, is a hallmark of many solid tumors and affects a range of cellular processes, including DNA repair. In low-oxygen conditions, cancer cells often suppress key DNA repair pathways such as homologous recombination (HR), leading to the accumulation of DNA damage and increased genomic instability. These changes not only drive tumor progression but also contribute to resistance against conventional therapies. Hypoxia significantly reduces the effectiveness of oxygen-dependent treatments, including radiotherapy and many chemotherapeutic a

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… CHK2 activation is based on Thr68 phosphorylation in a manner dependent not only on ATM but also MLH1 and NBN genes, encoding the DNA mismatch repair protein Mlh1 and the DSB repair factor nibrin, a component of the MRN complex [ 87 ]. …

Current advances of CRISPR-Cas technology in cell therapy.

CRISPR-Cas is a versatile genome editing technology that has been broadly applied in both basic research and translation medicine. Ever since its discovery, the bacterial derived endonucleases have been engineered to a collection of robust genome-editing tools for introducing frameshift mutations or base conversions at site-specific loci. Since the initiation of first-in-human trial in 2016, CRISPR-Cas has been tested in 57 cell therapy trials, 38 of which focusing on engineered CAR-T cells and TCR-T cells for cancer malignancies, 15 trials of engineered hematopoietic stem cells treating hemog

What's your poison? Impact of individual repair capacity on the outcomes of genotoxic therapies in cancer. Part II - information content and validity of biomarkers for individual repair capacity in the assessment of outcomes of anticancer therapy.

The individual variance in the efficiency of repair of damage induced by genotoxic therapies may be an important factor in the assessment of eligibility for different anticancer treatments, the outcomes of various treatments and the therapy-associated complications, including acute and delayed toxicity and acquired drug resistance. The second part of this paper analyses the currently available information about the possibilities of using experimentally obtained knowledge about individual repair capacity for the purposes of personalised medicine and healthcare.