DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: July 9, 2021

Abstract Genomic instability is the hallmark of various cancers with increasing accumulation DNA damage. The application radiotherapy and chemotherapy in cancer treatment typically based on this property cancers. However, adverse effects including normal tissues injury are also accompanied by chemotherapy. Targeted therapy has potential to suppress cells’ damage response through tailoring patients lacking specific functions. Obviously, understanding broader role repair became a basic attractive strategy for targeted therapy, particular, raising novel hypothesis or theory field basis previous scientists’ findings would be important future promising druggable emerging targets. In review, we first illustrate timeline steps roles promotion developed, then summarize mechanisms regarding associated highlighting proteins behind targeting that initiate functioning abnormally duo extrinsic harm environmental factors, also, baseline drift leads harmful intrinsic therapy. addition, clinical therapeutic drugs effects, as well scheme relative trials were intensive discussed. Based background, suggest two hypotheses, namely “environmental gear selection” describe pathway evolution, “DNA drift”, which may play magnified mediating during treatment. This new shed light provide much better more comprehensive holistic view promote development research direction overcoming strategies patients.

Language: Английский

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DNA Damage and Its Role in Cancer Therapeutics

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4741 - 4741

Published: March 1, 2023

DNA damage is a double-edged sword in cancer cells. On the one hand, exacerbates gene mutation frequency and risk. Mutations key repair genes, such as breast 1 (BRCA1) and/or 2 (BRCA2), induce genomic instability promote tumorigenesis. other induction of using chemical reagents or radiation kills cells effectively. Cancer-burdening mutations repair-related genes imply relatively high sensitivity to chemotherapy radiotherapy because reduced efficiency. Therefore, designing specific inhibitors targeting enzymes pathway an effective way synthetic lethality with therapeutics. This study reviews general pathways involved potential proteins that could be targeted for

Language: Английский

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Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2289 - 2289

Published: Jan. 24, 2023

The reduction in androgen synthesis and the blockade of receptor (AR) function by chemical castration AR signaling inhibitors represent main treatment lines for initial stages prostate cancer. Unfortunately, resistance mechanisms ultimately develop due to alterations pathway, such as gene amplification or mutations, also emergence alternative pathways that render tumor less or, more rarely, completely independent activation. An essential oncogenic axis activated cancer is phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target rapamycin (mTOR) evidenced frequent negative regulator phosphatase tensin homolog (PTEN) activating mutations PI3K subunits. Additionally, crosstalk reciprocal feedback loops between PI3K/AKT/mTOR cascade activate pro-survival signals play an role disease recurrence progression have been evidenced. Inhibitors addressing different players pathway evaluated clinic. Only a limited benefit has reported up now associated side effects, so novel combination approaches biomarkers predictive patient response are urgently needed. Here, we reviewed recent data on selective identified, most advanced clinical studies, with focus treatments. A deeper understanding complex molecular involved further guide therapeutic improved outcomes.

Language: Английский

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Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis

Molecular Oncology, Journal Year: 2024, Volume and Issue: 18(3), P. 726 - 742

Published: Jan. 15, 2024

Prostate cancer is a frequent malignancy in older men and has very high 5‐year survival rate if diagnosed early. The prognosis much less promising the tumor already spread outside prostate gland. Targeted treatments mainly aim at blocking androgen receptor (AR) signaling initially show good efficacy. However, progression due to AR‐dependent AR‐independent mechanisms often observed after some time, novel treatment strategies are urgently needed. Dysregulation of PI3K/AKT/mTOR pathway advanced its implication resistance been reported. We compared impact inhibitors with different selectivity profiles on vitro cell proliferation caspase 3/7 activation as marker for apoptosis induction, strongest effects androgen‐sensitive lines VCaP LNCaP. Combination AR inhibitor darolutamide led enhanced these lines, being most pronounced upon cotreatment pan‐PI3K copanlisib. A subsequent transcriptomic analysis performed cells revealed that combining copanlisib impacted gene expression more than individual treatment. comprehensive reversal response mTORC1 transcriptional programs well marked induction DNA damage was observed. Next, an vivo efficacy study using patient‐derived (PDX) model LuCaP 35 superior combined darolutamide. Importantly, immunohistochemistry treated tumors showed increased apoptosis, by elevated levels cleaved 3 Bcl‐2‐binding component (BBC3). In conclusion, data demonstrate concurrent blockade pathways antitumor induces PDX models.

Language: Английский

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Advances in PARP Inhibitors for Prostate Cancer

Cancers, Journal Year: 2023, Volume and Issue: 15(6), P. 1849 - 1849

Published: March 20, 2023

Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair. PARPi is a promising drug class that has gained significant traction the last decade with good outcomes different cancers. Several trials have sought to test its effectiveness metastatic castration resistant prostate cancer (mCRPC). We conducted comprehensive literature review evaluate current of this setting. To effect, we queries PubMed, Embase Cochrane databases. reviewed compared all major contemporary publications on topic. In particular, recent phase II III studies also demonstrated benefits olaparib, rucaparib, niraparib, talazoparib CRPC. Drug been assessed through radiological progression or overall response. Given notion synthetic lethality potential synergy other oncological therapies, several are looking integrate combined therapies. There remains ongoing controversy need for genetic screening prior treatment initiation as well optimal patient population, which would benefit most from PARPi. important asset arsenal mCRPC. New combinations may improve earlier phases cancer.

Language: Английский

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From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(11), P. 6281 - 6281

Published: June 3, 2022

Cancer arises following alterations at different cellular levels, including genetic and epigenetic modifications, transcription translation dysregulation, as well metabolic variations. High-throughput omics technologies that allow one to identify quantify processes involved in these changes are now available have been instrumental generating a wealth of steadily increasing data from patient tumors, liquid biopsies, tumor models. Extensive investigation integration led new biological insights into the origin development multiple cancer types helped unravel molecular networks underlying this complex pathology. The comprehensive quantitative analysis molecule class sample is named large-scale studies addressing prostate stages performed recent years. Prostate tumors represent second leading type prevalent cause death men worldwide. It very heterogenous disease so evaluating inter- intra-tumor differences will be essential for precise insight plasticity, but also personalized therapies. There ample evidence key role androgen receptor, steroid hormone-activated factor, driving early late disease, approval drugs diverse targets along pathway. Early genomic transcriptomic allowed determine genes regulated by signaling or other tumor-relevant pathways. More recently, they supplemented epigenomic, cistromic, proteomic metabolomic analyses, thus, our knowledge on intricate mechanisms involved, various levels regulation their interplay. approaches multi-omics analyses much deeper understanding pathways progression, response resistance This brings hope novel vulnerabilities identified, existing therapies more beneficial targeting population likely respond best, bespoke treatments with increased efficacy soon.

Language: Английский

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Targeting the stimulator of interferon genes (STING) in breast cancer

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: June 28, 2023

Breast cancer has a high occurrence rate globally and its treatment demonstrated clinical efficacy with the use of systemic chemotherapy immune checkpoint blockade. Insufficient cytotoxic T lymphocyte infiltration accumulation immunosuppressive cells within tumours are primary factors responsible for inadequate effectiveness breast treatment. The stimulator interferon genes (STING) represents pivotal protein in innate response. Upon activation, STING triggers activation enhancement adaptive functions, resulting therapeutic benefits malignant tumours. signalling pathway is influenced by various such as deoxyribonucleic acid damage response, tumour microenvironment, mitochondrial function. agonists gaining momentum research. This review provides comprehensive overview cyclic guanosine monophosphate-adenosine monophosphate synthase-STING pathway, agonists, latest findings related to their application cancer.

Language: Английский

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Targeting the DNA Damage Response for Cancer Therapy

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(21), P. 15907 - 15907

Published: Nov. 2, 2023

Over the course of long-term evolution, cells have developed intricate defense mechanisms in response to DNA damage; these play a pivotal role maintaining genomic stability. Defects damage pathways can give rise various diseases, including cancer. The (DDR) system is instrumental safeguarding accumulation and weakening DDR function both promote initiation progression tumors. Simultaneously, they offer opportunities targets for cancer therapeutics. This article primarily elucidates repair progress made targeting key proteins within treatment. Among them, poly (ADP-ribose) polymerase 1 (PARP1) plays crucial DDR, inhibitors PARP1 garnered extensive attention anticancer research. By delving into realms repair, we aspire explore more precise effective strategies therapy seek novel avenues intervention.

Language: Английский

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A review of non-classical MAPK family member, MAPK4: A pivotal player in cancer development and therapeutic intervention

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 271, P. 132686 - 132686

Published: May 25, 2024

Language: Английский

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Update of PSMA Theranostics in Prostate Cancer: Current Applications and Future Trends

Journal of Clinical Medicine, Journal Year: 2022, Volume and Issue: 11(10), P. 2738 - 2738

Published: May 12, 2022

There is now an increasing trend for targeting cancers to go beyond early diagnosis and actually improve Progression-Free Survival Overall Survival. Identifying patients who might benefit from a particular targeted treatment the main focus Precision Medicine. Radiolabeled ligands can be used as predictive biomarkers which confirm target expression by using positron emission tomography (PET). The same ligand subsequently labeled with therapeutic radionuclide therapy. This combined approach termed “Theranostics”. prostate-specific membrane antigen (PSMA) has emerged attractive diagnostic small molecule in prostate cancer. It either emitters PET-based imaging or beta alpha review article summarizes important concepts Medicine contributing improved therapy of cancer we identify some key learning points areas further research.

Language: Английский

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