To investigate the prevalence and intensity of symptoms in patients with colorectal cancer (CRC), and to develop a symptom network model to pinpoint key symptoms and clusters within the network.

Acute myeloid leukemia (AML) is the most prevalent type of leukemia in adults. Its heterogeneity, both between patients and within the same patient, is often a factor contributing to poor treatment outcomes. Despite advancements in AML biology and medicine in general, the standard AML treatment, the combination of cytarabine and daunorubicin, has remained the same for decades. Combination drug therapies are proven effective in achieving targeted efficacy while minimizing drug dosage and unintended side effects, a common problem for older AML patients. However, a systematic survey of the synergistic potential of drug-drug interactions in the context of AML pathology is lacking. Here, we examine the interactions between 15 commonly used cancer drugs across distinct AML cell lines and demonstrate that synergistic and antagonistic drug-drug interactions are widespread but not conserved across these cell lines. Notably, enasidenib and venetoclax, recently approved anticancer agents, exhibited the highest counts of synergistic interactions and the fewest antagonistic ones. In contrast, 6-Thioguanine, a purine analog, was involved in the highest number of antagonistic interactions. The interactions we report here cannot be attributed solely to the inherent natures of these three drugs, as each drug we examined was involved in several synergistic or antagonistic interactions in the cell lines we tested. Importantly, these drug-drug interactions are not conserved across cell lines, suggesting that the success of combination therapies might vary significantly depending on AML genotypes. For instance, we found that a single mutation in the TF1 cell line could dramatically alter drug-drug interactions, even turning synergistic interactions into antagonistic ones. Our findings provide a preclinical survey of drug-drug interactions, revealing the complexity of the problem.

We introduce click-controlled photouncaging, an innovative approach that synergizes click ligation with photocleavage to achieve biorthogonal, light-triggered bioactive molecule release across visible to near-infrared (NIR) wavelengths. Central to this approach is a novel amine protection and deprotection strategy utilizing Pt(IV) complexes. In this strategy, an azide-bearing clickable Pt(IV) moiety acts as a protecting group for amine-containing molecules (the ″cargo″) via a carbamate linkage. Subsequently, click ligation with a DBCO-tagged fluorescent antenna positions the antenna near the Pt(IV) core, transforming it into a photoactive protecting group (PPG) that can be fine-tuned to respond to visible or NIR light. When exposed to light, the antenna drives the photoreduction of the Pt(IV) linker, triggering deprotection and subsequently releasing the cargo molecule. To validate this approach, three Pt(IV) complexes were synthesized featuring amine-containing fluorescent reporters (coumarin, BODIPY) and a therapeutic molecule (Exatecan), and their functionality was validated in solution and cell cultures. Overall, this work introduces a novel, user-friendly, and versatile chemical tool for bioorthogonal, light-controlled activation of molecules in complex biological environments.

The lack of T cells in tumors is a major hurdle to successful immune checkpoint therapy (ICT). Therefore, therapeutic strategies promoting T cell recruitment into tumors are warranted to improve the treatment efficacy. Here, we report that Fc-optimized anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies are potent remodelers of tumor vasculature that increase tumor-associated high endothelial venules (TA-HEVs), specialized blood vessels supporting lymphocyte entry into tumors. Mechanistically, this effect is dependent on the Fc domain of anti-CTLA-4 antibodies and CD4+ T cells and involves interferon gamma (IFNγ). Unexpectedly, we find that the human anti-CTLA-4 antibody ipilimumab fails to increase TA-HEVs in a humanized mouse model. However, increasing its Fc effector function rescues the modulation of TA-HEVs, promotes CD4+ and CD8+ T cell infiltration into tumors, and sensitizes recalcitrant tumors to programmed cell death protein 1 (PD-1) blockade. Our findings suggest that Fc-optimized anti-CTLA-4 antibodies could be used to reprogram tumor vasculature in poorly immunogenic cold tumors and improve the efficacy of ICT.

Ferroptosis serves as a pivotal mechanism in diverse clinical chemotherapeutics and physiological processes, profoundly impacting tumor metabolism and the tumor microenvironment. Recently, the immunosuppression induced by ferroptosis has raised major concerns regarding tumor recurrence upon ferroptosis-based antitumor therapies. However, due to the lack of cell specificity, the antitumor and immunosuppressive effects in ferroptosis are inherently intertwined. Herein, we address the conflicting challenges between immunosuppression and antitumor efficacy in ferroptosis-based therapy by enabling cell-specific ferroptosis, thereby targeting tumors while sparing immune cells. By employing a specially designed nanoagent, i.e., ferrous selenide half-shell-covered gold, we induce notable upregulation of glutathione peroxidase 4 (GPX4) and downregulation of prostaglandin E2, leading to an increase in CD4+ and CD8+ T cell populations and intense antitumor immune responses. Despite the elevated level of GPX4, significant tumor cell ferroptosis is achieved, which is further promoted by the agent's photothermal and photocatalytic effects. Consequently, long-term immunological memory is established, yielding a long-lasting and recurrence-free antitumor efficacy spanning at least 200 days post-treatment. This work unlocks an avenue to balance immunosuppression reversal with tumor inhibition in ferroptosis-based therapies, providing promising prospects for antitumor therapies facing immunological hurdles in the tumor microenvironment.

Antibody-drug conjugates (ADCs) have emerged as a highly promising modality for the treatment of various tumors, including pancreatic cancer. Due to the modular nature of ADCs, their efficacy is heavily influenced by the choice of antibody, payload, and linker. Given the therapeutic potential of triptolide for pancreatic cancer, this study aims to harness triptolide as the cytotoxic payload to construct ADCs targeting pancreatic cancer. Silyl ethers were utilized for the first time as cleavable linkers to connect triptolide with an antibody. This is because silyl ethers can be easily synthesized and the rate of drug release can be regulated by modifying the silyl ether groups. The release profile of the resulting linkers was investigated. And considering the balance between cleavage and stability, one silyl ether-based linker was selected to prepare an ADC, named A10. Meanwhile, a traditional dipeptide linker-based ADC, A9, was synthesized for comparison. The ADC A10 demonstrated superior inhibitory effects compared to ADC A9, both in vitro and in vivo. A10 displayed targeted cytotoxicity against cells with high PD-L1 expression and demonstrated a bystander killing effect on cells with low PD-L1 expression. In vivo imaging studies indicated that fluorescently labeled A10 accumulated in tumor regions. Additionally, significant antitumor activities of A10 were observed against Panc 08.13-derived tumor xenografts.

Protein deubiquitination via deubiquitinases is a crucial aspect of the dynamic modification of biomacromolecules. The deubiquitinase USP7 plays a key role in tumorigenesis through diverse pathways, thus representing a promising novel target for anti-cancer therapies. In this paper, in order to find novel USP7 inhibitors, a series of compounds scaffold-hopping from the reported USP7 inhibitor CP41 were designed, synthesized and biologically evaluated. Most of them exhibited certain inhibition against the in vitro USP7 enzyme activity. The most potent compounds (X12, X16, X21, X22 and X23) were highly selective for USP7 over a panel of other tested DUBs and showed significant in vitro inhibition against cancer cell proliferation. Interestingly, in RS4; 11 cancer cells, the selected compound X21 not only regulated the level of the extensively studied proteins (e.g. MDM2, p53, TRIM27) but also remarkably reduced the protein level of PCLAF, a key factor involved in TLS. In colon cancer animal models, X21 exerted in vivo anti-tumor efficacy, probably through synergistic effects of direct cytotoxicity and immune microenvironment improvement. These findings may provide directions for future design of novel USP7 inhibitors and facilitate the exploration of new mechanism of USP7 inhibitors.

S-phase kinase-associated protein 2 (Skp2) is the vital component of the Skp1-Cullin 1-F-box (SCF) E3 ubiquitin ligase complex, which precisely regulates CDK inhibitors by coordinating with Cks1 and has been identified to be involved in the progression of many human malignancies. Inspired by our previous study, we designed novel 2,3-diarylpyrazine derivatives via molecular hybridization strategy to enhance Skp2-Cks1 inhibition. Compound 10h emerged as the most potent inhibitor, displaying an IC50 value of 0.38 μM against Skp2-Cks1 binding with 7.3- and 12.8-fold improvements over leads ZK-14i and HK-E35, respectively. Moreover, 10h demonstrated excellent anti-tumor activities against lung cancer NCl-H1299 and esophageal cancer KYSE-510 cells, inducing S-phase arrest and suppressing proliferation through targeting Skp2. Notably, 10h significantly increased the sensitivity of NCl-H1299 cells to cisplatin by suppressing the cell stemness. Overall, this study developed 10h as a potent Skp2 inhibitor and explored its effects on tumor treatment, especially in enhancing the efficacy of cisplatin during chemotherapy.

Sarcoidosis is a multisystemic granulomatous disease of uncertain etiology. Several drugs have been linked to the development of sarcoidosis or systemic granulomatous reactions indistinguishable from this disease. We present the clinical case of a patient diagnosed with breast cancer and undergoing treatment with capecitabine who, after developing systemic and musculoskeletal symptoms, was ultimately diagnosed with capecitabine-induced sarcoidosis.

Multidrug resistance (MDR) is one of the major problems in cancer treatment. Overcoming MDR to achieve effective cancer treatment remains a huge challenge. Here, we proposed a self-generative singlet oxygen (1O2)-initiated chemical modification of nuclear DNAs (SiCMoND) approach to kill multidrug-resistant tumor synergizing with chemotherapy. A tumor-targeted "nano-bomb" FA(CT-fT-Dox) was rationally fabricated by encapsulating the complex of Cu2+ with tetrakis(4-carboxyphenyl) porphyrin) (Cu-TCPP) as a 1O2 generator and a doxorubicin (Dox) prodrug tailed with a furan-containing positively charged peptide (fTAT-Dox) within the micelles of FA-PEG5000-PCL3000 and mPEG5000-PCL3000. When FA(CT-fT-Dox) nanoparticles accumulated at the tumor site, they could undergo disassembly in the tumor microenvironment (TME) specifically to release Cu-TCPP and fTAT-Dox simultaneously. Taking advantage of the features of Cu-TCPP that can convert tumor-abundant H2O2 into 1O2 and fTAT-Dox that can readily penetrate the cell membrane into the nucleus, chemical modification of nuclear DNAs was realized through the covalent cyclization reaction between furan and nucleobases of nuclear DNAs under the ignition of self-generative 1O2, which leads to significant DNA damage and enhanced therapeutic susceptibility. More notably, the sustained release of Dox within the nucleus greatly inhibits DNA transcription and translation leading to severe cancer cell apoptosis. In vivo studies in a multidrug-resistant MCF-7/ADR tumor model showed that the antitumor efficacy of FA(CT-fT-Dox) was 1.6-fold higher than FA(CT-T-Dox) without DNA modification functionality with a tumor suppression efficiency of 83.3%. This SiCMoND-assisting chemotherapy strategy provides a promising antitumor therapeutic modality and opens new avenues for battling multidrug-resistant tumors.

JAK2 is a promising target for treating myeloproliferative neoplasms (MPNs). However, existing JAK2 inhibitors cannot fully cure these diseases and may induce resistance with prolonged use. Here, we report the design, synthesis, and biological evaluation of a series of highly potent JAK2 degraders based on our previously developed inhibitor WWQ-131. The optimal compound 10i demonstrates a high degradation rate (DR) against JAK2 in SET-2 cells carrying the JAK2 V617F mutation, achieving a DR of 91.32% at 5 μM and a DC50 of 27.35 ± 5.36 nM. Moreover, 10i exhibits more potent antiproliferative activity against SET-2 cells than fedratinib and its parent inhibitor WWQ-131. Mechanistic studies reveal that 10i degrades JAK2 through the ubiquitin-protease pathway. Importantly, 10i suppresses rhEPO-mediated polycythemia and splenomegaly in mice by degrading JAK2 and interfering with the JAK2-STAT signaling pathway. Taken together, the results of this study reveal a promising JAK2 PROTAC degrader for the treatment of MPNs.

Lung cancer has the second highest occurrence and lowest survival rate among all cancers and incidence rates are increasing. From the tumor milieu, tumors exude chemokines and cytokines that hassle the pulmonary drug administration hinders the success of treatment. A few mutations lead to generation of lungs cancer. It has prominent levels of mutated genes such as TP53, KRAS, MET, and EGFR. Various molecular pathways involved in causing lung cancer such as PTEN/PI3K/AKT pathway, JAK/STAT pathways, RAF-MEK-ERK, PI3K-AKT-mTOR, and RALGDS-RA, PI3K, AKT, and PI3K/AKT/mTOR pathway. Inhibition of such biological pathway through active targeting, using various biological inhibitors, and blockers could help in treating and recurrence of lungs tumor. The conventional therapeutic modalities concomitant with personalized genomic nanomedicine can have potential in improving treatment regimen. This study explored the different genomic changes that occur due to the prime etiological factors, their reported treatment profile, and nanocarrier mediated therapeutic strategy by targeting tumor microenvironment (TME). Nanocarriers confront multiple obstacles in their journey to the TME therapeutic approach as leaky vasculature, large fenestration, and usually carried off from immune system and phagocytosis process. However, formulators designed a bio-functionalized carrier that enable to evade opsonization, escape immune system, modulate TME, identify reticuloendothelial system, and thus facilitates biological interaction, and enhance cellular uptake.

Recent approvals of polymeric adenosine diphosphate ribose (poly(ADP-ribose) polymerase inhibitors (PARPi) for BRCA-mutant metastatic castration resistant prostate cancer necessitate an understanding of the factors that shape sensitivity and resistance. Reversion mutations that restore homologous recombination (HR) repair are detected in ~50 to 80% of BRCA-mutant patients who respond but subsequently relapse, but there is currently little insight into why only ~50% of BRCA-mutant patients display upfront resistance. To address this question, we performed a genome-wide CRISPR screen to identify genomic determinants of PARPi resistance in murine Brca2Δ/Δ prostate organoids genetically engineered in a manner that precludes the development of reversion mutations. Remarkably, we recovered multiple independent single guide RNAs (sgRNAs) targeting three different members (Cdt1, Cdc6, and Dbf4) of the DNA prereplication complex (pre-RC), each of which independently conferred resistance to olaparib and the next-generation PARP-1 selective inhibitor AZD5305. Moreover, sensitivity to PARP inhibition was restored in Brca2Δ/Δ, Cdc6-depleted prostate cells by knockdown of geminin, a negative regulator of Cdt1, further implicating the critical role of a functional pre-RC complex in PARPi sensitivity. Furthermore, ~50% of CRPC tumors have copy number loss of pre-RC complex genes, particularly CDT1. Mechanistically, prostate cells with impaired pre-RC activity displayed rapid resolution of olaparib-induced DNA damage as well as protection from replication fork degradation caused by Brca2 loss, providing insight into how Brca2-mutant cancer cells can escape cell death from replication stress induced by PARP inhibition in the absence of HR repair. Of note, a pharmacologic inhibitor that targets the CDT1/geminin complex (AF615) restored sensitivity to AZD5305, providing a potential translational avenue to enhance sensitivity to PARP inhibition.

Point mutations in the androgen receptor (AR) are significant drivers of resistance in prostate cancer (PCa), posing a great challenge to the development of effective treatment strategies. Building on our previous discovery of the suboptimal AR antagonist T1-12, we developed LT16, which contains an N-(4-(benzyloxy)phenyl)piperidine-1-sulfonamide scaffold through structural optimization and comprehensive screening against T878A-mutated AR. LT16 outperformed existing antiandrogens by fully antagonizing clinical AR mutations and effectively suppressing castration- and enzalutamide-resistant LNCaP cells proliferation in vitro. Mechanically, LT16 was found to disrupt AR nuclear translocation, hinder AR homodimerization, and suppress transcription of AR-regulated genes by competitive binding to the ligand binding pocket. Further in vivo experiments demonstrated that LT16 significantly reduced both regular- and enzalutamide-resistant LNCaP tumor volume and serum prostate-specific antigen levels in mice. These findings position LT16 as a promising and innovative therapeutic for advanced PCa, particularly in cases where resistance to current therapies is a concern.

Drug combination therapy is an effective strategy for cancer treatment, enhancing drug efficacy and reducing toxic side effects. However, in vitro drug screening experiments are time-consuming and expensive, necessitating the development of computational methods for drug synergy prediction. While current methods focus on molecular chemical structures, they often overlook the biological context, limiting their ability to capture complex drug synergies.

Mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase belonging to the MET gene family. Aberrant c-Met signaling drives tumorigenesis. Acquired drug resistance to current type I c-Met inhibitors has limited their duration of response. Many type II inhibitors have been developed to address the on-target resistance mutations that render type I inhibitors ineffective. However, type II inhibitors, to date, have not been approved to treat c-Met-driven cancers due to poor selectivity and suboptimal physicochemical properties that limit free drug concentrations. Herein, we describe how structure-based drug design (SBDD) directed at optimization of lipophilic efficiency (LipE) enabled the discovery of a highly selective type IIb c-Met inhibitor with quality drug-like properties. Lead compound KIN-8741 exhibits broad potency against acquired resistance mutations and a desirable safety profile that supported the filing and clearance of an IND for the treatment of cancer.

The rising incidence and mortality rates of malignant tumors highlight their profound impact on human health. Bacterial therapy has emerged as a promising avenue in oncological research. Our lab has isolated an analgesic-anti-tumor peptide from the venom of Buthus martensii Karsch (BmK AGAP), a long-chain scorpion venom peptide, which exhibits remarkable anti-tumor activity. However, the limited bioavailability of peptides poses a challenge for their therapeutic efficacy. To address this challenge, we focused on enhancing the delivery of BmK AGAP to improve its anti-tumor effectiveness. We engineered E. coli K12 to create the TSYPU strain, which not only expresses BmK AGAP, but also possesses lytic capabilities. Co-culturing of TSYPU with murine breast cancer 4T1 cells in vitro demonstrated its potential as a drug delivery platform. Further advancements included the encapsulation of TSYPU with nanogold particles, resulting in TSYPU@Au strain. In vivo experiments revealed that TSYPU@Au exhibited a significant anti-tumor effect, crucially overcoming degradation in the acidic gastrointestinal environment. In summary, our study highlights the viability of engineered TSYPU bacteria as carriers for BmK AGAP delivery, offering a promising approach for the rational design of bacterial-based peptide drug delivery systems in oncology. This strategy has considerable potential for advancing the field and warrants further investigation in future studies.

Immune checkpoint blockade (ICB) immunotherapies are a powerful tool in the clinical management of cancer, but response rates to ICB remain limited, and treatment-related toxicities can be significant. Therapeutic efficacy of ICB can be enhanced by delivering synergistic immunomodulators to tumor-draining lymph nodes (TdLNs). However, achieving sustained release of small molecule immunomodulators into the lymphatics and TdLNs remains challenging. To address this limitation, a sustained release system for delivering an oligonucleotide adjuvant to lymph nodes (LNs) was developed. CpG oligonucleotide was complexed with a redox-responsive cationic polymer and mixed with F127-g-Gelatin to generate a thermosensitive hydrogel that releases lymph-draining polyplex micelles in situ. This CpG/BPEI-SS-/F127-g-Gelatin (CpG-HG) system enhanced the quantity and duration of CpG delivery to TdLNs following locoregional administration compared with free drug and enabled targeted, potent, and prolonged immunomodulation within TdLNs from a single administration. This augmented, localized immune response synergized with systemic ICB treatment, both markedly amplifying the systemic circulating CD8+ T cell response and improving antitumor therapeutic efficacy while enabling ICB dose reduction. These results highlight the potential for this drug delivery system as an adjunct to existing clinical ICB protocols to improve patient outcomes.

Despite the widespread use of chemotherapeutic agents, their reliance on apoptosis often limits therapeutic efficacy and leads to drug resistance. To overcome these challenges, alternative cell death mechanisms such as cuproptosis have gained significant attention. While previous studies have primarily focused on incorporation of Cu into nanostructures, this work presents the first example of a molecular tripodal Cu(II) complex as a potent cuproptosis inducer. Herein, a series of tripodal Cu(II) complexes were chemically synthesized and biologically evaluated. The most promising compound demonstrated remarkable cytotoxicity in the low micromolar to nanomolar range. Mechanistic studies revealed that the compound catalytically produced hydroxyl radicals in the mitochondria of cancerous cells, causing protein oligomerization and the disruption of iron-sulfur cluster proteins, ultimately triggering cell death by cuproptosis. Contrary to traditional chemotherapeutic agents that cause reduction in tumor size, this compound induced the fragmentation of three-dimensional tumor spheroids.

The development of bisubstrate molecules mimicking the transition state of RNA methylation offers a promising approach for modulating post-transcriptional processes. In this study, five SAM-adenosine conjugates were synthesized, each incorporating a SAM cofactor analog linked to the N1 position of adenosine via triazole- and amide-based connectors. Cellular assays demonstrate that these compounds were not cytotoxic at 10 μM on SW620 and MCF-7 human cancer cell lines. Notably, one conjugate significantly affected several mRNA methylation processes in colorectal SW620 cells at this concentration. Furthermore, four compounds inhibited sphere formation in both cancer cell lines, underscoring their potential as tools to modulate RNA methylation in oncogenic contexts and guide the design of new therapeutic agents.