MedComm – Oncology最新文献

Two recent companion papers published in Nature have reported two promising drug candidates, HRO761¹ and VVD-133214,² for microsatellite instability (MSI) cancers targeting the werner syndrome RecQ helicase (WRN), a synthetic lethal target in cancer cells with MSI. Currently, both candidates are undergoing clinical trials to evaluate their safety, tolerability, and preliminary antitumor activity in MSI patients.

Microsatellites, also known as short tandem repeats, are susceptible to slippage errors during replication, rendering them heavily reliant on the DNA mismatch repair (MMR) system. MMR deficiency results in widespread MSI by failing to correct replication errors, thus initiating cancer via aberrant tumor suppressor gene function. The prevalence of MSI ranges from 10% to 30% across multiple cancer types, such as colorectal, endometrial, ovarian, and gastric cancers.^1-3 In MSI tumors, deficiencies in MMR mechanisms heighten genomic instability, prompting the activation of alternative DNA repair pathways, including those implicating WRN. Inhibitors targeting WRN in MSI cancer cells, which already possess compromised DNA repair mechanisms, may induce synthetic lethality, thereby triggering DNA damage and subsequent cancer cell death. This targeted approach is ineffective against normal or microsatellite instability (MSS) cells, as their MMR mechanisms remain intact. Hence, WRN inhibitors emerge as a highly promising synthetic lethal agent, with the potential to selectively eradicate tumor cells while sparing normal cells (Figure 1A).

Novartis researchers reported HRO761,¹ a novel WRN helicase inhibitor (Figure 1B) which targets the ATPase of WRN as a noncovalent inhibitor. Cocrystal structures of HRO761 with WRN helicase revealed its binding to a nonconserved site at the D1–D2 interface, immobilizing WRN in an inactive conformation with an approximate 180° rotation relative to the adenosine triphosphate (ATP)-bound conformation (Figure 1C). Despite its 702 Da molecular weight, HRO761 displayed favorable physicochemical properties and pharmacokinetics (PK), with a clean off-target profile. In vitro cellular assays showed that HRO761 exhibits an IC₅₀ of 100 nM in ATPase assays at high ATP concentration, effectively impairing the viability of MSI cancer cells, while showing no effect in MSS cells. Furthermore, characterization of HRO761 treatment effects on MSI cells revealed time- and dose-dependent cell cycle arrest and DNA damage, regardless of p53 mutation status. In the SW48 cell-derived xenografts (CDX) model, oral administration of 15–60 mg/kg HRO761 resulted in significant tumor regression without observed toxicity. Additionally, combination therapy involving HRO761 with other antitumor drugs may enhance treatment efficacy and reduce side effects and resistance. In vivo studies show complete tumor regression with combi

In a recent study published in Nature Communications, Zhou et al. reported a sprayable, self-oxygenating hydrogel (HIL@Z/P/H), encapsulating photosynthetic cyanobacteria (PCC 7942), and tumor-targeted nanomedicine (HIL@Z), which could rapidly crosslink at the melanoma resection site, not only effectively inhibited tumor recurrence or metastasis but also aided in wound healing postsurgery.¹

Melanoma, a highly aggressive and metastatic cancer, predominantly relies on surgical intervention as its primary treatment modality. Despite surgical resection, the challenge persists in completely eradicating all malignant tissue, especially residual cells along the operative margins, which are particularly prone to triggering local recurrence.² As has been demonstrated, the hypoxic conditions at the surgical site promote the dissemination and distant metastasis of residual melanoma cells while perpetuating a chronic inflammatory state within the wound. This not only hampers the healing process but also constitutes a profound risk to the patient's survival and diminishes the quality of their postsurgical life.³ To minimize risks and accelerate wound recovery following surgery, radiotherapy, chemotherapy, and immunotherapy therapy are frequently employed as adjunctive treatments.^{4, 5} However, the therapeutic outcomes of these strategies often fall short of expectations and are accompanied by notable toxic side effects. Hence, the pursuit of efficacious strategies to alleviate the hypoxic microenvironment has emerged as a crucial goal.

Therefore, addressing the fundamental issue of the deteriorative hypoxic microenvironment after surgery that leads to tumor recurrence/metastasis and delayed wound healing, Zhou's group employed nanotechnology to design a therapeutic hydrogel (Figure 1A). Specifically, they noticed PCC 7942, microorganisms that harness a primitive photosynthetic system to produce oxygen in a lasting and controllable manner, making them a promising candidate to explore as an oxygen generator for alleviating hypoxia. Besides, they fabricated HIL@Z, which was composed of hyaluronic acid (HA), indocyanine green (ICG), L-arginine (L-Arg), and zeolite imidazole framework (ZIF-8). Next, they proceeded to encapsulate the PCC 7942 along with HIL@Z in situ at the surgical wound site by spraying a calcium alginate hydrogel. Noteworthy, the porous channels of the hydrogel facilitated nutrient and gas transport (Figure 1B), which can provide an ideal environment for PCC 7942 to support their long-term survival and thereby maintain consistent photosynthetic oxygenation. The photosynthetic oxygenation capability of HIL@Z/P/H did not show significant changes during 15 days of storage, demonstrating excellent stability in oxygenation efficiency (Figure 1C). After obtaining HIL@Z/P/H, Zhou and colleagues proceeded to further validate its func

Malignant pleural mesothelioma (MPM) is a malignant tumor of the pulmonary pleural tissue for which there is a lack of effective targeted therapy. In this study, moderate to high V-domain immunoglobulin T-cell activation suppressor (VISTA) expression levels were observed in most MPM clinical tumor samples. We prepared two high-affinity anti-VISTA monoclonal antibodies (mAbs) and generated two novel VISTA-targeted antibody-drug conjugates (ADCs) by conjugating anti-VISTA mAbs with the potent cytotoxic drug monomethyl auristatin E (MMAE). αV1-MMAE and αV2-MMAE showed potent killing effects to VISTA-positive cell lines in vitro, with half-maximal inhibitory concentration (IC₅₀) of nanomolar levels. αV1-MMAE and αV2-MMAE were also able to significantly induce apoptosis and cause G2/M phase arrest in VISTA-positive cells. In the VISTA-positive human MPM xenograft model, both αV1-MMAE and αV2-MMAE showed significant antitumor activity, led to a significant survival advantage compared to mice in the control group, and effectively induced apoptosis in the tumor tissues of mice. In conclusion, we demonstrated that the novel VISTA-targeted ADCs (αV1-MMAE and αV2-MMAE), especially αV1-MMAE, had potent killing effects against VISTA-positive MPM cells both in vitro and in vivo. Therefore, through further development, they may have the potential to become new drugs for the treatment of MPM.

The rapid progress in cancer treatment, along with the increase in cure and control rates, has led to the gradual acceptance of cancer as a chronic disease. Cancer treatment is comprehensive and long-term. However, cancer symptoms and treatment side effects can hinder patients' quality of life and adherence to treatment, ultimately impacrefting their long-term survival. Acupuncture (AC) and electro-acupuncture (EA) have been widely used to treat various diseases. AC and EA have demonstrated their ability to relieve symptoms and side effects related to cancer treatment. The review provides a brief overview of the historical lineage and basic principles of AC treatment, as well as a detailed exploration of the mechanisms and clinical applications of AC and EA to relieve cancer symptoms and treatment side effects. AC and EA can play a therapeutic role by regulating systems of nervous, endocrine, immune and so on. Clinical studies have demonstrated that AC and EA can effectively relieve pain, postoperative ileus, and other symptoms. The safety of AC and EA has been tested worldwide. Furthermore, we discuss the challenges and future research directions for AC and EA in the field of cancer treatment.

Infectious etiologies have previously been proposed as causes of both melanoma and non-melanoma skin cancer. This exploratory overview explains and presents the evidence for the hypothesis that a microorganism excreted in infected ruminant animal feces, Mycobacterium avium subspecies paratuberculosis (MAP), is the cause of some cases of cutaneous melanoma (CM). Occupational, residential, and recreational contact with MAP-contaminated feces, soil, sand, and natural bodies of water may confer a higher rate of CM. Included in our hypothesis are possible reasons for the differing rates and locations of CM in persons with white versus nonwhite skin, why CM develops underneath nails and in vulvar skin, why canine melanoma is an excellent model for human melanoma, and why the Bacille Calmette-Guérin (BCG) vaccine has demonstrated efficacy in the prevention and treatment of CM. The pathogenic mechanisms and etiologic aspects of MAP, as a transmittable agent underlying CM risk, are carefully deliberated in this paper. Imbalances in gut and skin bacteria, genetic risk factors, and vaccine prevention/therapy are also discussed, while acknowledging that the evidence for a causal association between MAP exposure and CM remains circumstantial.

Therapy resistance and recurrence are irrefutably ascribed to the unique attributes of the cancer stem cell (CSC) population. Therefore, discerning the underlying mechanism is imperative in arbitrating a strategic therapeutic approach. In this study, we have observed the coexistence of neuron-like cell (NLC) subpopulations in different cancer cell lines. The NLC subset was further validated by transfection studies and was found to be positive for PSD-95. As a proof of concept, we have also demonstrated the transpiration of neurological phenomena such as long-term potentiation (LTP) and long-term depression (LTD) in cancer. We have utilized PMA drug and IL-13 cytokine to study LTD and LTP, respectively, and observed a correlation between the memory marker (GLUN2B) and stemness markers (CD95 and CD58). Moreover, the transcriptional protein pCREB, which plays a crucial role in memory formation, was found to influence CD44 protein levels. These findings suggest that the instigation of LTD can impair cellular memory and sensitize CSC to the metabolic inhibitor, 3Bromopyruvate. Furthermore, this study interfaces the neurobiology of cancer and nanomedicine, wherein we have used biomimetic nanocarriers for the active targeting of drugs and demonstrate their ability to augment therapeutic efficiency.

Synthetic lethality (SL), a genetic concept, has revolutionized the development of antitumor therapies by providing avenues to target previously “undruggable” targets with enhanced specificity for tumor cells over normal tissue. The principles of SL have expanded beyond genetic definitions to encompass biological functions, including genome stability, cell cycle regulation, cell death mechanisms, cellular metabolism, cell–cell interactions, and the tumor microenvironment (TME). Tumor cells with inactivated survival pathways are sensitive to therapeutic inhibition of compensatory mechanisms, while normal cells remain unaffected. Exploiting SL based on functional contexts has the potential to significantly improve cancer patient survival by reducing resistance to targeted therapies and enhancing antitumor efficacy when combined with other treatment modalities. This review explores the underlying mechanisms of synthetic lethality interactions (SLI) characterized by biological functions in individual cancer cells and the TME. We also provide a comprehensive summary of strategies for leveraging the dynamic nature of SLI to overcome therapeutic resistance. Additionally, we discuss various approaches and models for screening and designing potent SL agents tailored to the specific needs of cancer patients, as well as strategies for combining SL drugs in tumor treatment. This review offers valuable insights into harnessing SL as a promising avenue for precision cancer therapy.

Janus Kinases (JAKs) play a crucial role as therapeutic targets for various cancers. However, the current JAK inhibitors (JAKi) available have limited therapeutic benefits due to their lack of selectivity. This review focuses on the structural analysis to elucidate the molecular determinants of JAKs specificity and the discovery and design of selective JAKi. It includes descriptions and comparison of different JAK structures and their binding sites, a comparative analysis of JAKi and their binding modes, detailed interaction fingerprints (IFPs), and an extensive structure-selectivity relationship (SSRs). Moreover, the review also explores the challenges and possibilities of using computational structure-based methods for discovering and designing selective JAKi. Other structure-based approaches, such as targeting the pseudokinase domain, as well as covalent and allosteric designs, are also covered. Based on this analysis, key determinants corresponding to JAK specificity and rational medicinal chemistry strategies are proposed to facilitate the development of highly selective JAKi. Overall, we aim to enhance the understanding of JAK specificity and explore strategies that can lead to the discovery of effective and selective JAKi in cancer therapy, thus improving the prognosis for cancer patients.

Rapid growth in nanoparticles (NPs) as delivery systems holds vast promise to promote therapeutic approaches for cancer treatment. Presently, a diverse array of NPs with unique properties have been developed to overcome different challenges and to achieve sophisticated delivery routes for enhancement of a series of therapies. Inspiring advances have been achieved in the field of cancer therapy using NPs. In this review, we aim to summarize the up-to-date progression of NPs for addressing various challenges, and expect to elicit novel and potential opportunities alternatively. We first introduce different sorts of NP technologies, illustrate their mechanisms, and present their applications. Then, the achievements made by NPs to break obstacles in delivering cargoes to specific sites through particular routes are highlighted, including long-circulation, tumor targeting, responsive release, and subcellular localization. We subsequently retrospect recent research of NPs in different cancer treatments from single therapy, like chemotherapy, to combination therapy, like chemoradiotherapy, and to integrative therapy. Finally, the challenges and perspectives of NPs in cancer therapy, and their potential impact on the field of oncology are discussed. We believe this review can offer a deeper understanding of the challenges and opportunities of NPs for cancer therapy.

The tumor microenvironment (TME) is the ecosystem surrounding a tumor, which usually consists of nontumoral cells or components, and molecules they produce and release. The frequent and continuous interplay between tumor cells and the TME strongly affects tumor development, disease progression, metastasis, and responses to therapeutic interventions. As a hub of potential therapeutic targets, the TME has gained appreciable momentum in cancer research. Here we systematically review the progress in targeting the TME as a strategy to develop novel antitumor drugs from the immunological, stromal and extracellular matrix components of the TME, shedding light on its complex synergies with tumor cells. This exploration highlights the transformative potential these elements hold in refining cancer treatment approaches. This thorough examination not only accentuates the TME's multifaceted nature but also positions it as a formidable avenue for propelling forward the paradigms of cancer therapy. This review aims to foster a deeper understanding of the TME's role in oncogenesis and its potential exploitation in advancing targeted, efficacious cancer treatments, marking a significant stride in the realm of cancer research.