PARP inhibitors have profoundly changed treatment options for cancers with homologous recombination repair defects, especially those carrying BRCA1/2 mutations. However, the development of resistance to these inhibitors presents a significant clinical challenge as it limits long-term effectiveness. This review provides an overview of the current understanding of resistance mechanisms to PARP inhibitors and explores strategies to overcome these challenges. We discuss the basis of synthetic lethality induced by PARP inhibitors and detail diverse resistance mechanisms affecting PARP inhibitors, including homologous recombination restoration, reduced PARP trapping, enhanced drug efflux, and replication fork stabilization. The review then considers clinical approaches to combat resistance, focusing on combination therapies with immune checkpoint inhibitors, DNA damage response inhibitors, and epigenetic drugs. We also highlight ongoing clinical trials and potential biomarkers for predicting treatment response and resistance. The review concludes by outlining future research directions, emphasizing the need for longitudinal studies, advanced resistance monitoring technologies, and the development of novel combination strategies. By tackling PARP inhibitor resistance, this review seeks to aid in the development of more effective cancer therapies, with the potential to improve outcomes for patients with homologous recombination-deficient tumors.

Soft tissue sarcoma (STS) is a rare, heterogeneous malignancy with limited treatment options for metastatic disease. Despite advances in immunotherapy, including PD-1 inhibitors, clinical outcomes remain suboptimal, highlighting the need for novel biomarkers and therapeutic strategies. This study investigated the role of TACC2 in STS, focusing on its impact on the immune microenvironment and immunotherapy response.

A series of novel diphenylamine fluorinated chalcone derivatives (B1-B10) were synthesized and characterized using 1H and 13C NMR, IR, and MS, and purity was determined using HPLC. The compounds were evaluated for their antimicrobial, antimalarial, and anticancer activities, with Chloramphenicol, Griseofulvin, and 5-Fluorouracil serving as standard reference drugs. Notably, B6 exhibited excellent antifungal activity, comparable to that of the standard drug Griseofulvin. Compounds B3 and B5 showed strong antimalarial effects against Plasmodium falciparum. Both B3 and B5 exhibit substantial cytotoxicity against HeLa cells, with IC50 values of 24.53 µg/ml for B5 and 32.42 µg/ml for B3. These results clearly demonstrate that both compounds outperform the standard drug 5-Fluorouracil, establishing their strong potential as effective alternatives in cancer therapy. Molecular docking studies revealed that B3 and B6 effectively interacted with the active site of Falcilysin, while B5 and B7 showed favourable binding to proteins 6GUE and 2 × 7 F. Molecular dynamics simulations confirmed the stability of B3 and B6 with P. falciparum, while B5 and B3 exhibited promising interactions with 6GUE and 2X7F. These results suggest that compounds B3 and B5 are potential lead candidates for developing novel antimicrobial, antimalarial, and anticancer therapies.

To update the systematic review of assessment tools on chemotherapy-induced peripheral neuropathy (CIPN) for pediatric oncology patients based on the evidence available after the published review in 2020.

First-line immune checkpoint inhibitor (ICI) combinations show responses in subsets of hepatocellular carcinoma (HCC) patients. Nearly half of HCCs are Wnt-active with mutations in CTNNB1 (encoding for β-catenin), AXIN1/2, or APC, and demonstrate heterogeneous and limited benefit to ICI due to an immune excluded tumor microenvironment. We show significant tumor responses in multiple β-catenin-mutated immunocompetent HCC models to a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1). Both single-cell and spatial transcriptomics reveal cellular and zonal reprogramming, along with activation of immune regulatory transcription factors IRF2 and POU2F1, re-engaged type I/II interferon signaling, and alterations in both innate and adaptive immunity upon β-catenin suppression with LNP-CTNNB1 at early- and advanced-stage disease. Moreover, ICI enhances response to LNP-CTNNB1 in advanced-stage disease by preventing T cell exhaustion and through formation of lymphoid aggregates (LA). In fact, expression of an LA-like gene signature prognosticates survival for patients receiving atezolizumab plus bevacizumab in the IMbrave150 phase III trial and inversely correlates with CTNNB1-mutatational status in this patient cohort. In conclusion, LNP-CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through impacting tumor cell-intrinsic signaling and remodeling global immune surveillance, providing rationale for clinical investigations.

This study presents the development of 177Lu-labeled polymeric nanoparticles (PNPs) for theranostic applications in head and neck cancer, utilizing both near-infrared II (NIR-II) and SPECT imaging for targeted delivery and monitoring. The PNPs were surface-modified with ethylenediamine and chelated with DTPA to enable 177Lu radiolabeling, achieving a radiochemical yield of 15.4% ± 3.2% and high purity (>95%). The radiolabeling process preserved the size distribution and optical properties of PNPs, facilitating their use in NIR-II imaging, which confirmed effective tumor delivery with peak uptake at 24 h postinjection. Photothermal therapy (PTT) combined with 177Lu-PNPs significantly enhanced tumor uptake and therapeutic efficacy, as shown by tumor growth suppression and extended survival in treated mice. Importantly, mice receiving the 177Lu-PNPs-PTT combination therapy exhibited minimal toxicity, as indicated by stable body weight and unaltered organ histology on H&E staining. These findings demonstrate the potential of 177Lu-PNPs as a safe and effective multifunctional platform for imaging-guided photothermal-radionuclide cancer therapy.

Metabolic heterogeneity resulting from the intra-tumoral heterogeneity mediates massive adverse outcomes of tumor therapy, including chemotherapeutic resistance, but the mechanisms inside remain largely unknown. Here, we find that the de novo pyrimidine synthesis pathway determines the chemosensitivity. Chemotherapeutic drugs promote the degradation of cytosolic Carbamoyl-phosphate synthetase II, Aspartate transcarbamylase, and Dihydroorotase (CAD), an enzyme that is rate-limiting for pyrimidine synthesis, leading to apoptosis. We also find that CAD needs to be cleaved by caspase-3 on its Asp1371 residue, before its degradation. Overexpressing CAD or mutating Asp1371 to block caspase-3 cleavage confers chemoresistance in xenograft and Cldn18-ATK gastric cancer models. Importantly, mutations related to Asp1371 of CAD are found in tumor samples that failed neoadjuvant chemotherapy and pharmacological targeting of CAD-Asp1371 mutations using RMY-186 ameliorates chemotherapy efficacy. Our work reveals the vulnerability of de novo pyrimidine synthesis during chemotherapy, highlighting CAD as a promising therapeutic target and biomarker.

Marsdenia tenacissima extract (MTE) from the stem of the Traditional Chinese herbal medicine of Marsdenia tenacissima (Roxb.) Wight et Arn. has been used as an anticancer remedy for decades.

Alemtuzumab is a powerful anti-CD52 drug that is an established treatment option in patients with multiple sclerosis due to its proven efficacy. However, in about 50% of patients, the use of alemtuzumab is burdened by the development of secondary autoimmune thyroid diseases, constituting a range of alemtuzumab-induced autoimmune thyroid diseases (AIATDs). Graves' disease (GD) is the most common AIATD, with an incidence of approximately 60%, and presents different characteristics from the conventional form. Indeed, GD with a fluctuating course is significantly more prevalent (15-50%), which poses a major challenge for physicians in its management. Other AIATDs also exhibit distinct features compared to their conventional counterparts; notably, hypothyroidism is frequently associated with TSH-receptor blocking antibodies, and alemtuzumab-induced GD demonstrates a higher rate of fluctuating course and potential for spontaneous remission. Alemtuzumab-induced thyroid eye disease (TED) is less common than conventional TED, with similar clinical and management characteristics. In this review, we summarize the latest evidence, also from real-world studies, with a focus on clinical management and possible predictors of AIATDs.

The aim of this study was to reveal the hepatotoxicity profile of different immune checkpoint inhibitor (ICI) used strategies in patients with Hepatocellular carcinoma (HCC) by meta-analysis.

Cancer is a multifaceted disease that occurs when cells proliferate and migrate in an uncontrolled and unregulated manner. The development of cancer is the result of the interaction of a number of factors, including genetic mutations, environmental factors and lifestyle habits. There are many pharmacological and natural compounds that can be used to prevent and/or treat cancer. Piperine, a naturally occurring compound with multiple therapeutic properties, is the primary bioactive component of black pepper (Piper nigrum L.), a member of the Piperaceae plant family. In recent years, it has attracted much interest as a potentially useful agent for the preventive and curative management of cancer. Results from studies of human cancer cell lines and advanced animal tumour models suggest that there are multiple pathways by which piperine may affect cancer development and metastasis. This review examines the molecular and cellular mechanisms through which piperine exerts its effects on cancer formation and progression, as well as its potential effects on various types of cancer.

Indenoisoquinolines are a class of topoisomerase I (TOP1) inhibitors designed to overcome clinical limitations of camptothecins. Three indenoisoquinolines (LMP400, LMP776, and LMP744) demonstrated activity in murine models and a comparative canine lymphoma study. Clinical data for LMP400 were previously reported (NCT01051635). The maximum tolerated dose (MTD), safety, and clinical data from phase 1 studies of LMP776 (NCT01051635) and LMP744 (NCT03030417) are reported herein.

Myeloid neoplasms-post cytotoxic therapy (MN-pCT, previously therapy-related myeloid neoplasms/tMN), are secondary malignancies associated with prior chemotherapy treatment, historically carrying a very poor prognosis. These are rarely associated with primary central nervous system (CNS) tumors, usually high-grade CNS malignancies requiring intensive multimodal treatment. Pediatric low-grade gliomas (pLGGs) are the most common childhood CNS tumors, and up to 50% of patients will require adjuvant therapy, which has traditionally consisted of low-dose metronomic chemotherapy, though the recent identification of key molecular drivers of pLGG means targeted therapies are changing this paradigm. We present a novel case of a 17-year-old girl with therapy-related myelodysplastic syndrome following chemotherapeutic treatment for pLGG. Given the poor prognosis of MN-pCTs, this case represents an important note of caution when choosing appropriate therapy for pLGG, especially considering the evolving role for targeted treatments in this disease.

IntroductionDrug-induced myelosuppression (DIM) is a serious side effect of several medications, particularly chemotherapy, immunosuppressants, and targeted therapies, which can lead to infections, anemia, and bleeding. While these drugs are effective, their adverse effects can disrupt treatment plans and reduce quality of life. However, early identification of DIM remains challenging, as many associated drugs do not explicitly list this risk, complicating clinical monitoring.MethodsThis study utilized the FDA Adverse Event Reporting System (FAERS) database to perform signal mining and assess the risks of DIM. Reports from the first quarter of 2004 to the third quarter of 2024 were analyzed using signal detection algorithms such as Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). These methods helped identify drug signals related to DIM and explore risk factors and occurrence patterns.ResultsThe study analyzed 21 380 adverse event reports related to DIM, showing a significant increase in the number of reports since 2019, peaking at 3501 in 2021. Among patients, 50.2% were female, 35.5% were male, and the majority (44.42%) were aged between 18 and 65. Breast cancer patients had the highest DIM incidence (10.6%). Geographically, China reported the most cases (57.4%), followed by Japan (12.4%), and the United States (6.76%). The drugs most frequently linked to DIM included trastuzumab, bevacizumab, venetoclax, methotrexate, and pertuzumab. Additionally, 12 new drug signals were identified that were not labeled for DIM risk, including PERTUZUMAB, SODIUM CHLORIDE, and MESNA, which showed particularly strong or unexpected associations.ConclusionThis study identifies new DIM-related drug signals and emphasizes the need for early detection to improve clinical management and optimize treatment regimens. The findings provide valuable evidence for drug safety monitoring and can help reduce DIM-related risks in cancer treatment.

Globally, lung cancer continues to be the primary cause of both cancer incidence and death. The disease is multifaceted, influenced by numerous external factors and the individual's genetic or epigenetic predisposition to its onset and timing. Upon diagnosis, fewer than one-third of patients present with localized disease amenable to curative multimodal therapy; the remainder have metastatic disease. Currently, numerous treatments are ineffective due to resistance to standard medications or the emergence of distant metastases. Plant-derived natural compounds have garnered significant attention in recent years due to their high permeability and low toxicity. Piper longum, Piper nigrum, Zingiber officinalis, Emblica officinale, Terminalia bellirica, Terminalia chebula, Drynaria quercifolia, Phyllanthus amarus, and Eclipta prostrata are traditional Indian herbs with diverse pharmacological properties. This study assessed the efficacy of active chemicals from the polyherbal formulation on lung cancer target proteins by molecular docking. Preliminary and qualitative phytochemical Antioxidant testing indicated significant pharmacological effects. Moreover, the formulation exhibited modest anti-inflammatory and significant apoptotic action. These findings validate the therapeutic effectiveness of this polyherbal mixture for cancer treatment. Nonetheless, it is imperative to perform further preclinical research to elucidate the mechanisms of action of the molecule, as well as its pharmacodynamic and pharmacokinetic features.

Cancer remains a global health challenge, and natural plant-based compounds show potential in prevention. Calligonum polygonoides Linn., a drought- and frost-resistant shrub native to the Thar desert, has adaptive resilience and ethnomedicinal applications. This study explores C. polygonoides stem extract (CPSE) against DMBA-induced two stage skin carcinogenesis in male Swiss albino mice.

Metastatic breast cancer (MBC) remains a major cause of cancer-related mortality, with limited treatment options in advanced stages. Eribulin is now recommended for MBC and covered by the Indonesian National Health Insurance Policy as monotherapy for 6 cycles. However, data on its effectiveness and safety in Indonesian patients remain scarce. This study aimed to evaluate the disease control rate, overall survival (OS), and adverse events of eribulin monotherapy after 6 treatment cycles in Indonesian MBC patients.

Bioprospecting of indigenous plants for biological/cytotoxic properties has become an area of growing interest in cancer research. Wrightia tinctoria is a lesser-studied plant widely distributed in India which is commonly used in traditional medicinal systems like Ayurveda and Siddha and holds potential as a source for novel therapeutic agents. In this study, the cytotoxic effects of Wrightia tinctoria bark extracts on oral cancer (KB) cell lines were evaluated, focusing on three different extraction solvents ethanol, ethyl acetate, and water. The present study aimed to evaluate and compare the cytotoxic effects of Wrightia tinctoria bark extracts, while also investigating their potential to induce apoptosis which can contribute into exploration of new plant based anticancer agents.

In the era of precision medicine, a molecularly targeted therapeutical approach is still missing in the field of neuroendocrine neoplasms (NENs) other than for radioligand therapy (RLT). So far sunitinib is the only tyrosine kinase inhibitor (TKI) available in clinical practice for NENs in Western countries, limited to advanced, progressing pancreatic neuroendocrine tumors (NETs). A few TKIs worldwide reached an advanced stage of clinical investigation with promising results.

Pleural mesothelioma (PM) is an aggressive cancer caused by asbestos exposure, with limited treatment options and poor prognosis, highlighting the need for more effective therapies. Combining immune checkpoint blockade with anti-angiogenic therapy has shown potential in other cancers. Our study investigated the combined inhibition of PD-L1 and VEGFR2 in a mouse model of PM. Using C57BL/6 mice with subcutaneous AE17 mesothelioma tumors, we assessed the effects of anti-PD-L1 therapy with induction, concomitant, or consolidation anti-VEGFR2 treatment. Mice received intraperitoneal doses every three days for three treatments. Tumor growth, survival, tumor-infiltrating immune cells and intra-tumoral vasculature were analyzed. Results demonstrated that combining anti-PD-L1 with induction or concomitant anti-VEGFR2 significantly delayed tumor growth, improved survival, and promoted vascular maturation. Flow cytometry suggested T cell exhaustion in monotherapy groups, while no significant changes were seen with concomitant treatment. Depleting CD4+ T cells reversed the positive effects of concomitant treatment. These findings suggest that dual inhibition of PD-L1 and VEGFR2 is a promising therapeutic approach for PM, with CD4+ T cells playing a critical role in the immune response. This dual targeting of immune checkpoints and angiogenesis offers a potential new avenue for improving outcomes in PM treatment and warrants further clinical exploration.