Molecular Cancer Therapeutics

There is an unmet clinical need to develop novel strategies to overcome resistance to tyrosine kinase inhibitors (TKIs) in patients with oncogene-driven lung adenocarcinoma (LUAD). The objective of this study was to determine if simvastatin could overcome TKI resistance using the in vitro and in vivo LUAD models. Human LUAD cell lines, tumor cells, and patient-derived xenografts (PDXs) from TKI-resistant LUAD were treated with simvastatin, either alone or in combination with a matched TKI. Tumor growth inhibition was measured by the MTS assay and expression of molecular targets was assessed by immunoblots...

Radioresistance of melanoma brain metastases limits the clinical utility of conventionally fractionated brain radiation in this disease, and strategies to improve radiation response could have significant clinical impact. The catalytic subunit of DNA-dependent protein kinase (DNA- PKcs) is critical for repair of radiation-induced DNA damage, and inhibitors of this kinase can have potent effects on radiation sensitivity. In this study, the radiosensitizing effects of the DNA-PKcs inhibitor peposertib were evaluated in patient-derived xenografts (PDXs) of melanoma brain metastases (M12, M15, M27)...

Mutations within the oncogene KRAS drive an estimated 25% of all cancers. Only allele-specific KRAS G12C inhibitors are currently available and are associated with the emergence of acquired resistance, partly due to upstream pathway reactivation. Given its upstream role in the activation of KRAS, Son of Sevenless homologue 1 (SOS1), has emerged as an attractive therapeutic target. Agents that target SOS1 for degradation could represent a potential pan-KRAS modality that may be capable of circumventing certain acquired resistance mechanisms...

PROTACs (proteolysis targeting chimeras) are an emerging precision medicine strategy that targets key proteins for proteolytic degradation to ultimately induce cancer cell killing. These hetero-bifunctional molecules hijack the ubiquitin proteasome system to selectively add polyubiquitin chains onto a specific protein target to induce proteolytic degradation. Importantly, PROTACs have the capacity to target virtually any intracellular and transmembrane protein for degradation, including oncoproteins previously considered undruggable, which strategically positions PROTACs at the crossroads of multiple cancer research areas...

Geranylgeranyl diphosphate synthase (GGDPS), the source of the isoprenoid donor in protein geranylgeranylation reactions, has become an attractive target for anticancer therapy due to the reliance of cancers on geranylgeranylated proteins. Current GGDPS inhibitor development focuses on optimizing the drug-target enzyme interactions of nitrogen-containing bisphosphonate-based drugs. To advance GGDPS inhibitor development, understanding the enzyme structure, active site, and ligand/product interactions is essential...

The small molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), elimusertib, is currently being tested clinically in various cancer entities in adults and children. Its preclinical anti-tumor activity in pediatric malignancies, however, is largely unknown. We here assessed the preclinical activity of elimusertib in 38 cell lines and 32 patient-derived xenograft (PDX) models derived from common pediatric solid tumor entities. Detailed in vitro and in vivo molecular characterization of the treated models enabled the evaluation of response biomarkers...

Histone deacetylase inhibitors (HDACis) are part of a growing class of epigenetic therapies used for the treatment of cancer. Although HDACis are effective in the treatment of T-cell lymphomas, treatment of solid tumors with this class of drugs has not been successful. Overexpression of the multidrug resistance protein P-glycoprotein (P-gp), encoded by ABCB1, is known to confer resistance to the HDACi romidepsin in vitro, yet increased ABCB1 expression has not been associated with resistance in patients, suggesting that other mechanisms of resistance arise in the clinic...

Brain metastasis from lung cancer is a prevalent mode of treatment failure associated with a poor prognosis. The incidence of brain metastasis has recently shown a dramatic increase. The early detection and risk stratification of lung cancer-related brain metastasis would be highly advantageous for patients. However, our current knowledge and comprehension of the underlying mechanisms driving brain metastasis in lung cancer pose significant challenges. This review summarizes the mechanisms underlying brain metastasis, focusing on the intricate interplay between lung cancer-derived tumor cells and the unique characteristics of the brain, recent advancements in the identification of driver genes, concomitant genes, epigenetic features, including microRNAs and long non-coding RNAs, as well as the molecular characterization of brain metastasis originating from other organs, which may further enhance risk stratification and facilitate precise treatment strategies...

The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant leave unmet needs for patients with or without resistance mutations in ESR1, the gene that encodes the ER protein...

Anticancer nucleosides are effective against solid tumors and hematological malignancies, but typically are prone to nucleoside metabolism resistance mechanisms. Using a nucleoside-specific multiplexed high-throughput screening approach, we discovered 4'-ethynyl-2'-deoxycytidine (EdC) as a third-generation anticancer nucleoside prodrug with preferential activity against diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). EdC requires deoxycytidine kinase (DCK) phosphorylation for its activity and induced replication fork arrest and accumulation of cells in S-phase, indicating it acts as a chain terminator...

We evaluated the efficacy and safety of TAS0313, a multi-epitope long peptide vaccine, plus pembrolizumab in post-chemotherapy immune checkpoint inhibitor-naïve patients with locally advanced/metastatic urothelial carcinoma. TAS0313 9 mg was administered subcutaneously followed by pembrolizumab 200 mg on Day 1, and as monotherapy on Day 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in 21-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety...

BTK and PI3K inhibitors are among the drugs approved for the treatment of patients with lymphoid neoplasms. Although active, their ability to lead to long-lasting complete remission is rather limited, especially in the lymphoma setting. This indicates that tumor cells often develop resistance to the drugs. We started from a marginal zone lymphoma cell line, Karpas-1718, kept under prolonged exposure to the PI3Kδ inhibitor idelalisib until acquisition of resistance, or with no drug. Cells underwent transcriptome, miRNA and methylation profiling, whole-exome sequencing, and pharmacologic screening, which led to the identification of the overexpression of ERBB4 and its ligands HBEGF and NRG2 in the resistant cells...

Although great strides have been made in the management and treatment of hepatocellular carcinoma (HCC), its prognosis is still poor yielding a high mortality. Immunotherapy is recommended for treating advanced HCC, but its efficiency is hampered due to hepatic immunosuppression. Stimulator of interferon genes (STING) pathway, serving as a critical cytoplasmic DNA-sensing process, is reported to initiate the anti-tumor immune response, and link the innate immunity to the adaptive immune system. Radiotherapy (RT) has been well acknowledged to induce destruction and release of tumor-derived DNA into the cytoplasm, which then activates the cGAS-STING pathway...

No abstract text is available yet for this article.

Diffuse intrinsic pontine gliomas (DIPG) are an incurable childhood brain cancer for which novel treatments are needed. DIPGs are characterized by a mutation in the H3 histone (H3K27M), resulting in loss of H3K27 methylation and global gene dysregulation. TRX-E-009-1 is a novel anticancer agent with preclinical activity demonstrated against a range of cancers. We examined the antitumor activity of TRX-E-009-1 against DIPG neurosphere cultures and observed tumor-specific activity with IC50s ranging from 20 to 100 nmol/L, whereas no activity was observed against normal human astrocyte cells...

Interleukin-12 (IL-12) is a proinflammatory cytokine, that has shown promising anti-tumor activity in humans by promoting the recruitment and activation of immune cells in tumors. However, the systemic administration of IL-12 has been accompanied by considerable toxicity, prompting interest in researching alternatives to drive preferential IL-12 bioactivity in the tumor. Here, we have generated XTX301, a tumor-activated IL-12 linked to the human Fc protein via a protease cleavable linker that is pharmacologically inactivated by an interleukin-12 receptor subunit beta 2 (IL-12Rβ2) masking domain...

Resistance to taxane chemotherapy is frequently observed in metastatic prostate cancer. The androgen receptor (AR) is a major driver of prostate cancer and a key regulator of the G1-S cell cycle checkpoint, promoting cancer cell proliferation by irreversible passage to the S-phase. We hypothesized that AR signaling inhibitor (ARSi) darolutamide in combination with docetaxel could augment antitumor effect by impeding the proliferation of taxane-resistant cancer cells. We monitored cell viability in organoids, tumor volume and PSA secretion in patient-derived xenografts (PDXs) and analyzed cell cycle and signaling pathway alterations...

In castrate-resistant prostate cancer (CRPC), increased glucocorticoid receptor (GR) expression and ensuing transcriptional activity have been proposed as an oncogenic "bypass" mechanism in response to androgen receptor (AR) signaling inhibition (ARSi). Here, we report that GR transcriptional activity acquired following ARSi is associated with the upregulation of cyclic adenosine monophosphate (cAMP)-associated gene expression pathways in both model systems and metastatic PC patient samples. In the context of ARSi, the expression of GR-mediated genes encoding cAMP signaling pathway-associated proteins can be inhibited by treatment with selective GR modulators (SGRMs)...

Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate. IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of IDHmt glioma and CCA patients...

The regulation of cellular processes by ion channels has become central to the study of cancer mechanisms. Designing molecules that can modify ion channels specific to tumor cells is a promising area of targeted drug delivery and therapy. Despite their potential in drug discovery, venom peptides - a group of natural products - have largely remained understudied and under-characterized. In general, venom peptides display high specificity and selectivity for target ion channels. Therefore, they may represent an effective strategy for selectively targeting the dysregulation of ion channels in tumor cells...