Combination Therapy Strategies Research Articles

Carrier free nanomedicine for synergistic cancer therapy by initiating apoptosis and paraptosis

Although photodynamic therapy (PDT) has been well-known as a promising anti-tumor treatment, its limited therapeutic efficiency remains to be a large challenge. In this study, a carrier free nanomedicine (designated as PyroMor) is developed to greatly initiate cell apoptosis and paraptosis for synergistic cancer therapy. Pyropheophorbide-a (Pyro) and morusin (Mor) are capable of self-assembling into PyroMor, which has been testified to have superiority of improved stability, cellular internalization, and biocompatibility. Because of efficient cellular uptake behavior, PyroMor could induce cellular paraptosis by Mor-caused vacuolation in mitochondria, ER and cytoplasm, contributing to improving the PDT efficacy of Pyro. Therefore, self-delivery PyroMor is able to accomplish synergistic anti-tumor effect via stimulation of cell apoptosis as well as paraptosis. In addition, in vivo studies also clarify that PyroMor presents passive tumor targeting delivery, leading to robust repressive effect on tumor proliferation with negligible systemic toxicity. This strategy of combined cancer therapy by initiating both cell apoptosis and paraptosis extremely benefits to the development of precise and effective cancer therapy in clinic.

Intracellular marriage of bicarbonate and Mn ions as \u201cimmune ion reactors\u201d to regulate redox homeostasis and enhanced antitumor immune responses

BackgroundDifferent from Fe ions in Fenton reaction, Mn ions can function both as catalyst for chemodynamic therapy and immune adjuvant for antitumor immune responses. In Mn-mediated Fenton-like reaction, bicarbonate ({text{HCO}}_{3}^{ - }), as the most important component to amplify therapeutic effects, must be present, however, intracellular {text{HCO}}_{3}^{ - } is strictly limited because of the tight control by live cells.ResultsHerein, Stimuli-responsive manganese carbonate-indocyanine green complexes (MnCO3-ICG) were designed for intracellular marriage of bicarbonate and Mn ions as “immune ion reactors” to regulate intracellular redox homeostasis and antitumor immune responses. Under the tumor acidic environment, the biodegradable complex can release “ion reactors” of Mn2+ and {text{HCO}}_{3}^{ - }, and ICG in the cytoplasm. The suddenly increased {text{HCO}}_{3}^{ - } in situ inside the cells regulate intracellular pH, and accelerate the generation of hydroxyl radicals for the oxidative stress damage of tumors cells because {text{HCO}}_{3}^{ - } play a critical role to catalyze Mn-mediated Fenton-like reaction. Investigations in vitro and in vivo prove that the both CDT and phototherapy combined with Mn2+-enhanced immunotherapy effectively suppress tumor growth and realize complete tumor elimination.ConclusionsThe combination therapy strategy with the help of novel immune adjuvants would produce an enhanced immune response, and be used for the treatment of deep tumors in situ.

Molecular Stacking Composite Nanoparticles of Gossypolone and Thermodynamic Agent for Elimination of Large Tumor in Mice via Electrothermal‐Thermodynamic‐Chemo Trimodal Combination Therapy

AbstractTo further improve the comprehensive therapeutic effect for large tumors, tumor cell membrane‐camouflaged molecular stacking composite nanoparticles (APGn@Mem NPs) are prepared by molecular stacking of chemotherapeutic drug gossypolone (Gn), thermodynamic agent (2,2'‐azobis[2‐(2‐imidazolin‐2‐yl) propane] dihydrochloride (AIPH)), polyvinyl alcohol, and phase change material lauric acid, which show a clear core–shell structure with a size of 65 ± 9.8 nm, high drug loading, low toxicity, homologous targeting, and thermal‐responsive release property. A type of micro‐electrothermal needle (MEN) with precise temperature control in situ (temperature range: mean value T ± 7 °C) is designed as the assistant heating system for APGn@Mem NPs. Subsequently, an elaborate tumor combination therapy strategy of electrothermal‐thermodynamic‐chemo trimodal combination therapy is developed through APGn@Mem NPs combined with the temperature control of MEN. Under MEN heating in situ, AIPH is rapidly released and generates abundant free radicals for short‐term electrothermal and thermodynamic therapy, while the release of Gn is relatively slow for long‐term chemotherapy. For large tumors (≈300 mm3) of nude mice, such combination therapy achieves remarkable comprehensive therapeutic efficacy with the 16‐day tumor inhibition rate of 99.89% and the 60‐day tumor recurrence rate of 20%, indicating this combination therapy has the prominent advantage and potential application in future.

FGFR4 inhibitors for the treatment of hepatocellular carcinoma: a synopsis of therapeutic potential

Introduction The mainstay pharmacological approaches to patients with hepatocellular carcinoma (HCC) are tyrosine kinase inhibitors, antiangiogenic agents, and immune checkpoint inhibitors in combination therapy. Aberrant signaling of fibroblast growth factor 19 (FGF19), and its corresponding receptor, fibroblast growth factor receptor 4 (FGFR4) are a driver of HCC cell growth and survival. However, the clinical potential of agents targeting aberrant FGF19/FGFR4 signaling has not been adequately explored. Areas covered We evaluate the existing literature on aberrant signaling of FGF19/FGFR4 in HCC and address the recent preclinical and clinical advances of selective FGFR4 inhibitors in the treatment of advanced HCC. Our literature search was performed in September 2021 on clinical trials and ongoing studies published in journals or presented in conferences for cancer research. Expert opinion Preclinical studies show selective FGFR4 inhibitors to be highly potent. These inhibitors also show promise in clinical trials and demonstrate manageable on-target side effects. An emphasis should be placed on the development of predictive biomarkers and on enhancing the understanding of primary and acquired resistance mechanisms. This will inspire rationale combination therapy strategies for testing in future clinical trials.

Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor.

Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Over 30 targeted inhibitors currently in preclinical and clinical trials have significant inhibitory effects on various tumors, including acute myelogenous leukemia (AML), diffuse large B cell lymphoma, prostate cancer, breast cancer and so on. However, resistance frequently occurs, revealing the limitations of BET inhibitor (BETi) therapy and the complexity of the BRD4 expression mechanism and action pathway. Current studies believe that when the internal and external environmental conditions of cells change, tumor cells can directly modify proteins by posttranslational modifications (PTMs) without changing the original DNA sequence to change their functions, and epigenetic modifications can also be activated to form new heritable phenotypes in response to various environmental stresses. In fact, research is constantly being supplemented with regards to that the regulatory role of BRD4 in tumors is closely related to PTMs. At present, the PTMs of BRD4 mainly include ubiquitination and phosphorylation; the former mainly regulates the stability of the BRD4 protein and mediates BETi resistance, while the latter is related to the biological functions of BRD4, such as transcriptional regulation, cofactor recruitment, chromatin binding and so on. At the same time, other PTMs, such as hydroxylation, acetylation and methylation, also play various roles in BRD4 regulation. The diversity, complexity and reversibility of posttranslational modifications affect the structure, stability and biological function of the BRD4 protein and participate in the occurrence and development of tumors by regulating the expression of tumor-related genes and even become the core and undeniable mechanism. Therefore, targeting BRD4-related modification sites or enzymes may be an effective strategy for cancer prevention and treatment. This review summarizes the role of different BRD4 modification types, elucidates the pathogenesis in the corresponding cancers, provides a theoretical reference for identifying new targets and effective combination therapy strategies, and discusses the opportunities, barriers, and limitations of PTM-based therapies for future cancer treatment.

Peptide-based long-acting co-agonists of GLP-1 and cholecystokinin 1 receptors as novel anti-diabesity agents

The combined use of gastrointestinal hormones for treating metabolic diseases is gaining increasing attention. It was documented previously that co-administration of a cholecystokinin receptor-1 receptor (CCK-1R) agonist with a glucagon-like peptide-1 receptor (GLP-1R) agonist exerted improved effects on metabolic improvements in obese rodents. Here, we reported a series of novel GLP-1R/CCK-1R co-agonists constructed by linking the C-terminus of a GLP-1R agonist (native GLP-1 or Xenopus GLP-1) to the N-terminus of a CCK-1R selective agonist NN9056. The stability of co-agonists was further enhanced by introducing an albumin binding motif. In vitro functional assays revealed that the co-agonists retained full agonism potency on GLP-1R and CCK-1R. Particularly, 2a and 2c showed higher hypoglycemic and insulinotropic activities than NN9056 and semaglutide. The glucose-lowering durations and PK profiles of 2a and 2c were comparable to those of semaglutide. Desirably, in diet induced obesity (DIO) mice, 2a and 2c exhibited superior metabolic benefits to NN9056 and semaglutide in reducing food intake, inducing body weight loss, and regulating lipid metabolism. In short- and long-term studies in diabetic db/db mice, 2a and 2c showed enhanced effects on HbA1c, glucose tolerance, and pancreas function restoration compared with semaglutide. Importantly, no side effects, toxicities, or pancreatic inflammation were caused by 2a and 2c treatments. These preclinical studies suggest that the pharmacological effects of CCK-1 and GLP-1 pathways can be harnessed in a single fusion peptide, yielding a promising combination therapy strategy for treating metabolic disorders.

Ag nanoparticles enhance immune checkpoint blockade efficacy by promoting of immune surveillance in melanoma

Immune checkpoint blockade (ICB) therapy, represented by programmed cell death protein 1 (PD-1) and its ligand (PD-L1) monoclonal antibodies (mAbs), has shown an obvious benefit for melanoma immunotherapy, but the overall response rate is still low. To find an effective combination therapy strategy, we successfully produced small size silver nanoparticles coated with sucrose (S-AgNPs) as potent adjuvants. The antitumor effects of S-AgNPs were tested in vitro and comparatively investigated in immunodeficient and immunocompetent mice with melanoma. Fluorescence-activated cell sorting and immunofluorescent staining analysis were conducted to identify the tumor microenvironments. The expression of PD-L1 in tumors was tested by multiple methods. The combination therapy and potential toxicity of S-AgNPs and PD-1 mAbs were assessed in melanoma-bearing mice. In our findings, S-AgNPs presented potent antitumor effects, good druggability and low systemic toxicity. Functionally, we found that S-AgNPs exhibited better antitumor effects in immunocompetent mice. Mechanistically, we showed that S-AgNPs suppress tumor cell proliferation by inducing cellular apoptosis and promote cytotoxic CD8+ T cell infiltration and activity. Preclinically, S-AgNPs showed excellent local antitumor activity and mild systemic immunotoxicity with PD-1 mAbs in the inhibition of melanoma proliferation, providing a novel clinical combination treatment strategy.

Abstract P1-16-07: A synthetic lethality treatment strategy for p53 mutant breast cancer

Abstract Breast carcinomas commonly carry mutations in the tumor suppressor p53, while therapeutic efforts to target mutant p53 were largely unfruitful. Here we report preclinical data supporting a novel combination therapy strategy for treatment of p53-mutant cancers. Genomic data revealed a high expression activity of Base-Excision Repair (BER) pathways in p53-mutant breast cancers. We designed a new methodology for testing BER in live cells. The BER studies revealed a significant dysregulation in BER-mediated repair in p53-mutant cancer cells. Taken advantage in the BER defect, we developed a novel treatment strategy that specifically targets p53-mt cancers. We found that treatment with deoxyuridine analogues induced accumulation of DNA damage selectively in p53-mutant cells. Further, inhibitors of poly (ADP-ribose) polymerase (PARPi) greatly enhanced this response and increased cell death, although PARPi as a single agent was not effective. In contrast, normal cells responded to PARPi with activation of the p53-p21 axis and cell cycle arrest. Inactivation of p53 in p53 wild-type cell lines conferred the p53-mutant phenotype. Preclinical breast cancer studies revealed that the combination of deoxyuridine analogue with PARPi was more effective in inhibition of tumor growth and metastases than either drug alone. This work illustrates a novel combination therapy strategy that may improve survival rates and outcomes for thousands of breast cancer patients. Citation Format: Andrei Bakin, Justin Zonneville, Moyi Wang, Mohammed Alruwaili, Kevin Eng, Renuka Iyer, Ben Park, Christos Fountzilas. A synthetic lethality treatment strategy for p53 mutant breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-07.

Dysregulated lipid metabolism blunts the sensitivity of cancer cells to EZH2 inhibitor.

SummaryBackgroundSensitivity has been a key issue for Enhancer of zeste homolog 2 (EZH2) inhibitors in cancer therapy. The EZH2 inhibitor EPZ-6438 was first approved by the US Food and Drug Administration (FDA) in 2020. However, its inadequate anti-cancer activity in solid tumors limits its clinical application. In this study, we utilized the multiple cancer cell lines, which are less sensitive to the EZH2 inhibitor GSK126, combining animal model and clinical data to investigate the underlying mechanism.MethodsIncuCyte S3 was used to explore the difference in the responsiveness of hematological tumor cells and solid tumor cells to GSK126. Transcriptome and metabolome of B16F10 cells after GSK126 treatment were analyzed and the distinct changes in the metabolic profile were revealed. Real-time quantitative PCR and western blot experiments were used to further verify the multi-omics data. ChIP-qPCR was performed to detected H3K27me3 enrichment of target genes. Finally, the anti-tumor effects of combining GSK126 and lipid metabolism drugs were observed with IncuCyte S3 platform, CCK-8 and animal model respectively.FindingsWe found that although the proliferative phenotype did not show strong difference upon treatment with GSK126, the transcriptome and metabolome changed profoundly. GSK126 treatment led to broad shifts in glucose, amino acid, and lipid metabolism. Lipid synthesis was strengthened manifested by the increasing abundance of unsaturated fatty acids. SCD1 and ELOVL2 were regulated by H3K27me3 at gene regulatory region, and upregulated by EZH2 knockdown and inhibitors. SCD1 knockdown increased cellular sensitivity to GSK126. Based on the findings above, the application of the combination with SCD1 inhibitor significantly attenuated the proliferation of cancer and increased the sensitivity to GSK126 by suppressing desaturation of fatty acids.InterpretationDysregulated lipid metabolism can blunt the sensitivity of cancer cells to GSK126. These characteristics shed light on the novel combination therapy strategies to combat tumor resistance.FundingNational Natural Science Foundation of China (No. 81672091, No.91749107 and No. 81972966).

Experimental Combination Therapy with Amiodarone and Low-Dose Benznidazole in a Mouse Model of Trypanosoma cruzi Acute Infection.

ABSTRACTChagas disease (CD), caused by Trypanosoma cruzi, affects approximately 6 to 7 million people in Latin America, with cardiomyopathy being the clinical manifestation most commonly associated with patient death during the acute phase. The etiological treatment of CD is restricted to benznidazole (Bz) and nifurtimox (Nif), which involve long periods of administration, frequent side effects, and low efficacy in the chronic phase. Thus, combined therapies emerge as an important tool in the treatment of CD, allowing the reduction of Bz dose and treatment duration. In this sense, amiodarone (AMD), the most efficient antiarrhythmic drug currently available and prescribed to CD patients, is a potential candidate for combined treatment due to its known trypanocidal activity. However, the efficacy of AMD during the acute phase of CD and its interaction with Bz or Nif are still unknown. In the present study, using a well-established murine model of the acute phase of CD, we observed that the Bz/AMD combination was more effective in reducing the peak parasitemia than both monotherapy treatments. Additionally, the Bz/AMD combination reduced (i) interleukin-6 (IL-6) levels in cardiac tissue, (ii) P-wave duration, and (iii) frequency of arrhythmia in infected animals and (iv) restored gap junction integrity in cardiac tissue. Therefore, our study validates AMD as a promising candidate for combined therapy with Bz, reinforcing the strategy of combined therapy for CD.IMPORTANCE Chagas disease affects approximately 6 to 7 million people worldwide, with cardiomyopathy being the clinical manifestation that most commonly leads to patient death. The etiological treatment of Chagas disease is limited to drugs (benznidazole and nifurtimox) with relatively high toxicity and therapeutic failures. In this sense, amiodarone, the most effective currently available antiarrhythmic drug prescribed to patients with Chagas disease, is a potential candidate for combined treatment due to its known trypanocidal effect. In the present study, we show that combined treatment with benznidazole and amiodarone improves the trypanocidal effect and reduces cardiac damage in acutely T. cruzi-infected mice.

Evaluation of JQ1 Combined With Docetaxel for the Treatment of Prostate Cancer Cells in 2D- and 3D-Culture Systems.

Introduction: Prostate cancer (PCa) is dependent on coupled androgen-androgen receptor (AR) signaling for growth and progression. Significant efforts have been made in this research field, as hormonal therapies have greatly improved the survival of patients with metastatic PCa (mPCa). The drug treatment agent JQ1, which potently abrogates bromodomain 4 (BRD4) localization to the AR target loci and therefore significantly impairs AR-mediated gene transcription, is a potent therapeutic option for patients with advanced PCa. In this study, we aimed to investigate the inhibitory effect of JQ1 combined with docetaxel on PCa cells in vitro for the first time. Furthermore, the 3D spheroid culture system was modeled to more accurately simulate the response of PCa cells to drugs. Methods: We established and measured 3D LNCaP spheroids in vitro in order to evaluate the susceptibility of 2D- and 3D-cultured LNCaP cells exposed to the same anti-cancer drug. Results: We demonstrated that JQ1 was an effective drug for promoting cell inhibition after docetaxel treatment in 2D- and 3D- cultured LNCaP cells. Inhibition of 3D cultured formation in the combined treatment group was significantly higher than that in docetaxel or JQ1 alone. Under the same conditions of drug solubility, the drug resistance of 3D spheroids was significantly higher than that of 2D cells. Moreover, dmax and lg volume were suitable parameters for LNCaP cells/spheroid size displaying and evaluating cell viability. Conclusion: 3D cultured spheroids of PCa are an effective tool for studying PCa drug trials. JQ1 combined with docetaxel may be an effective treatment for advanced PCa. This combination therapy strategy deserves further evaluation in clinical trials.

A prospective clinical trial of camrelizumab in combination with chemoradiotherapy in patients with metastatic esophageal squamous cell carcinoma.

326 Background: Patients with metastatic esophageal squamous cell carcinoma (mESCC) have dismal prognosis, immune checkpoint inhibitors (ICIs) have been reported to offer objective response rate (ORR) of approximately 30% with a median progression-free survival (PFS) of 3.6 months for mESCC. Emerging evidence suggests that radiation might be a potent immunomodulator in multiple malignancies. In this trial, we aimed to assess the efficacy and safety of the combination of camrelizumab with radiotherapy and chemotherapy in mESCC. Methods: Patients with ECOG performance status of 0-1 and normal renal, liver and bone marrow function who initially diagnosed with mESCC or progressed after prior systemic treatments were received camrelizumab 200 mg of 21-day cycles plus radiotherapy (30-50Gy/10-25f) and platinum-based combination chemotherapy. The primary endpoint was disease control rate (DCR); secondary endpoints were PFS, overall survival (OS), objective response rate (ORR) and safety. Chinese Clinical Trial Registry identifier: ChiCTR2000040533. Results: From September 2018 to March 2021, 34 patients (85.3% men; median age, 60 years; 85.3% ECOG PS=1; 61.8% ≥2 organ metastases) were recruited. At a median follow-up of 14.3 months, the DCR was 70.6% (24 of 34; 95%CI, 52.3 to 84.3); ORR was 38.2% (13 of 34; 95%CI, 22.7 to 56.4); 44.1% had decrease in measurable disease; ≥6 months clinical benefit rate (CBR) was 41.2% (14 of 34; 95%CI, 25.1 to 59.2). Median PFS and OS of 9.5 months (95% CI, 7.1 to NR) and 19.5 months (95% CI, 13.9 to NR), respectively. Of the 34 patients, 32 (94.1%) had treatment-related adverse events (TRAEs) of any grade and 13 (38.3%) had grade 3-4 TRAEs that including reactive cutaneous capillary endothelial proliferation (17.6%), myelotoxicity (23.5%) and interstitial pneumonia (2.9%). No treatment-related death occurred. To the cut-off date of observation, 15 (44.1%) patients died and 12 (35.3%) are still receiving the treatment without events. Conclusions: The combination of camrelizumab with radiotherapy and chemotherapy has notable efficacy compared with historical controls in mESCC with manageable safety. This combination therapy strategy should be validated in a larger trial in the future. Variable N=34 Clinical trial information: ChiCTR2000040533. [Table: see text]

Efficacy analysis of regorafenib combined with PD-1 inhibitors in elderly patients with metastatic colorectal cancer.

105 Background: Recently, an increasing number of patients (pts) with advanced colorectal cancer tend to receive regorafenib plus PD-1 inhibitors. However, there is a lack of information regarding real world effects of this therapeutic strategy, especially in elderly Chinese pts. We aimed to investigate the treatment patterns, clinical outcomes and prognostic factors of regorafenib plus PD-1 inhibitors therapy to Chinese elderly pts with advanced colorectal cancer. Methods: Retrospective analysis of a cohort of pts with advanced colorectal cancer received treatment of regorafenib combined with PD-1 inhibitors enrolled in our institution between January 2019 and January 2021. Among them, pts with 60 years or older were included in our final analysis. Overall survival (OS) and progression free survival (PFS) were estimated by Kaplan Meier curves, and other endpoints included objective response rate, prognostic factors. Results: At a median follow-up of 16.2 months, a total of 24 pts were enrolled in a real-world dataset from Henan Cancer Hospital. The median age was 68 years; 62.5% were female. The median OS and PFS were 15.03 months (95% CI 7.0-23.0) and 4.0 months (95% CI 1.8-6.2), respectively. 2/24 partial responses (PR) observed (ORR = 8.3%); Stable disease (SD) was obtained in 15/24. Disease control rate (PR plus SD) was therefore obtained in 17/24 (70.8%). When compared with PFS and OS in different initial daily doses group of regorafenib (such as ≤80, 120 or 160 mg), we concluded that there were no significantly difference between these groups. And similar results were found in final daily doses groups. However, it showed a trend toward better PFS in pts with ≥120 mg final daily doses group compared to <120 mg group (median PFS was 3.5 months in <120mg group versus 10.0 months in ≥120mg group). Median OS of pts for male gender demonstrated increasing trends compared with those female gender (20.2 months in males versus 13.2 months in females). Pts with previous treated with regorafenib had longer median OS than those without it (20.2 months versus 13.2 months). There were no obvious correlation for survival between pts only had liver metastasis and lung metastasis (P>0.05). No significant associations for survival could be seen in other tumor sites, K-RAS status, any kind of PD-1 inhibitors and whether previously treated with bevacizumab (P>0.05). Conclusions: This real-world dataset confirms that Chinese elderly pts with advanced colorectal cancer also can benefit from treatment of regorafenib combined with PD-1 inhibitors, similarly with this combination therapy strategies in all age pts. Furthermore, a longer survival time were obtained in pts with prior treated with regorafenib. The result also suggests that pts with ≥120mg final daily doses group had better PFS. However, further larger cohorts research should investigate whether the PFS advantage in high dose group could eventually lead to improved OS outcomes.

Co-delivery of paclitaxel and doxorubicin using polypeptide-engineered nanogels for combination therapy of tumor

Loading of chemotherapeutic agents into nanoparticles has been demonstrated to be an effective strategy for cancer therapy. However, simultaneous delivery of different functional drugs to tumor sites for chemotherapy still remains challenging. In this study, nanogels formed by an engineered coiled-coil polypeptide PC10A were designed and prepared as a carrier for co-delivery of paclitaxel (PTX) and doxorubicin (DOX) through ultrasonic treatment and electrostatic adsorption. The drug loading content and encapsulation efficiency of PTX and DOX in the PC10A/PTX/DOX nanogels were 5.98 wt%, 70 wt%, and 8.55 wt%, 83 wt%, respectively. Because the polypeptide PC10A was non-toxic and biodegradable, the PC10A/PTX/DOX nanogels exhibited good biocompatibility. The in vitro and in vivo antitumor experiments showed that the PC10A/PTX/DOX nanogels possessed obviously synergistic therapy effect of tumors and lower side effects compared with free PTX/DOX. Therefore, the PC10A/PTX/DOX nanogels are promising to provide a new strategy for combination therapy of different functional drugs.

Acidity-Activated Charge Conversion of 177Lu-Labeled Nanoagent for the Enhanced Photodynamic Radionuclide Therapy of Cancer.

Nanomaterials in combination with radionuclide therapy (RNT) provide new opportunities for cancer treatment. However, nanomaterials with efficient tumor accumulation have been less exploited for effective radionuclide-based therapy. Here, we report glycol chitosan-based nanoparticles (GCP-NPs) with acidic pH-dependent surface charge conversion for efficient radionuclide-based combination therapy. The nanoplatform can change the surface charge of nanoparticles from slight negative to positive in the acidic tumor microenvironment, which facilitates cellular internalization and penetration and thus improves the tumor accumulation efficiency of nanomaterials. Radiolabeling of GCP-NPs with 99mTc enables in vivo radioactive imaging in the mouse subcutaneous tumor model, showing 8.1-fold enhanced tumor uptake relative to pH-insensitive control nanoparticles (termed as GCOP-NPs). Afterward, therapeutic radioisotope 177Lu-labeled GCP-NPs (177Lu-GCP-NPs) that utilize RNT synergistic with photodynamic therapy (PDT) derived from conjugated pyropheophorbide-a within nanoparticles endow superior antitumor efficacy in living cells and tumor-bearing mouse model. More importantly, the combination of RNT and PDT using 177Lu-GCP-NPs can effectively inhibit lung metastasis and eliminate splenomegaly, which is not possible for individual RNT or PDT. Therefore, this study proposes a facile radionuclide-based combination therapy strategy toward complete cancer remission.

Targeting KRAS in Non-Small Cell Lung Cancer.

Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is the most frequently altered oncogene in Non-Small Cell Lung Cancer (NSCLC). KRAS mutant tumors constitute a heterogeneous group of diseases, different from other oncogene-derived tumors in terms of biology and response to treatment, which hinders the development of effective drugs against KRAS. Therefore, for decades, despite enormous efforts invested in the development of drugs aimed at inhibiting KRAS or its signaling pathways, KRAS was considered to be undruggable. Recently, the discovery of a new pocket under the effector binding switch II region of KRAS G12C has allowed the development of direct KRAS inhibitors such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, initiating a new exciting era. However, treatment with targeted KRAS G12C inhibitors also leads to resistance, and understanding the possible mechanisms of resistance and which drugs could be useful to overcome it is key. Among others, KRAS G12C (ON) tricomplex inhibitors and different combination therapy strategies are being analyzed in clinical trials. Another area of interest is the potential role of co-mutations in treatment selection, particularly immunotherapy. The best first-line strategy remains to be determined and, due to the heterogeneity of KRAS, is likely to be based on combination therapies.

Metabolic Implications of Immune Checkpoint Proteins in Cancer.

Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.

Engineering a multi-target therapy nanoplatform against tumor growth and metastasis via a novel NSAID-Pt(IV) prodrug.

Tumor growth and metastasis are caused by many factors. The complexity means that a multi-target combination therapy strategy should be selected against tumor growth and metastasis. Here, cisplatin (CDDP) and bendazac (Ben) were designed as a novel NSAID-Pt(IV) nanoplatform, which is an effective weapon for combating tumor growth and metastasis.

A combination therapy strategy for treating antibiotic resistant biofilm infection using a guanidinium derivative and nanoparticulate Ag(0) derived hybrid gel conjugate.

Bacteria organized in biofilms show significant tolerance to conventional antibiotics compared to their planktonic counterparts and form the basis for chronic infections. Biofilms are composites of different types of extracellular polymeric substances that help in resisting several host-defense measures, including phagocytosis. These are increasingly being recognized as a passive virulence factor that enables many infectious diseases to proliferate and an essential contributing facet to anti-microbial resistance. Thus, inhibition and dispersion of biofilms are linked to addressing the issues associated with therapeutic challenges imposed by biofilms. This report is to address this complex issue using a self-assembled guanidinium–Ag(0) nanoparticle (AD-L@Ag(0)) hybrid gel composite for executing a combination therapy strategy for six difficult to treat biofilm-forming and multidrug-resistant bacteria. Improved efficacy was achieved primarily through effective biofilm inhibition and dispersion by the cationic guanidinium ion derivative, while Ag(0) contributes to the subsequent bactericidal activity on planktonic bacteria. Minimum Inhibitory Concentration (MIC) of the AD-L@Ag(0) formulation was tested against Acinetobacter baumannii (25 μg mL−1), Pseudomonas aeruginosa (0.78 μg mL−1), Staphylococcus aureus (0.19 μg mL−1), Klebsiella pneumoniae (0.78 μg mL−1), Escherichia coli (clinical isolate (6.25 μg mL−1)), Klebsiella pneumoniae (clinical isolate (50 μg mL−1)), Shigella flexneri (clinical isolate (0.39 μg mL−1)) and Streptococcus pneumoniae (6.25 μg mL−1). Minimum bactericidal concentration, and MBIC50 and MBIC90 (Minimum Biofilm Inhibitory Concentration at 50% and 90% reduction, respectively) were evaluated for these pathogens. All these results confirmed the efficacy of the formulation AD-L@Ag(0). Minimum Biofilm Eradication Concentration (MBEC) for the respective pathogens was examined by following the exopolysaccharide quantification method to establish its potency in inhibition of biofilm formation, as well as eradication of mature biofilms. These effects were attributed to the bactericidal effect of AD-L@Ag(0) on biofilm mass-associated bacteria. The observed efficacy of this non-cytotoxic therapeutic combination (AD-L@Ag(0)) was found to be better than that reported in the existing literature for treating extremely drug-resistant bacterial strains, as well as for reducing the bacterial infection load at a surgical site in a small animal BALB/c model. Thus, AD-L@Ag(0) could be a promising candidate for anti-microbial coatings on surgical instruments, wound dressing, tissue engineering, and medical implants.

Optimal treatment strategy of cancers with intratumor heterogeneity.

Intratumor heterogeneity hinders the success of anti-cancer treatment due to the interaction between different types of cells. To recapitulate the communication of different types of cells, we developed a mathematical model to study the dynamic interaction between normal, drug-sensitive and drug-resistant cells in response to cancer treatment. Based on the proposed model, we first study the analytical conclusions, namely the nonnegativity and boundedness of solutions, and the existence and stability of steady states. Furthermore, to investigate the optimal treatment that minimizes both the cancer cells count and the total dose of drugs, we apply the Pontryagin's maximum(or minimum) principle (PMP) to explore the combination therapy strategy with either quadratic control or linear control functionals. We establish the existence and uniqueness of the quadratic control problem, and apply the forward-backward sweep method (FBSM) to solve the optimal control problems and obtain the optimal therapy scheme.