Combination Cancer Therapy Research Articles

Personalized tumor combination therapy optimization using the single-cell transcriptome

BackgroundThe precise characterization of individual tumors and immune microenvironments using transcriptome sequencing has provided a great opportunity for successful personalized cancer treatment. However, the cancer treatment response is often characterized by in vitro assays or bulk transcriptomes that neglect the heterogeneity of malignant tumors in vivo and the immune microenvironment, motivating the need to use single-cell transcriptomes for personalized cancer treatment.MethodsHere, we present comboSC, a computational proof-of-concept study to explore the feasibility of personalized cancer combination therapy optimization using single-cell transcriptomes. ComboSC provides a workable solution to stratify individual patient samples based on quantitative evaluation of their personalized immune microenvironment with single-cell RNA sequencing and maximize the translational potential of in vitro cellular response to unify the identification of synergistic drug/small molecule combinations or small molecules that can be paired with immune checkpoint inhibitors to boost immunotherapy from a large collection of small molecules and drugs, and finally prioritize them for personalized clinical use based on bipartition graph optimization.ResultsWe apply comboSC to publicly available 119 single-cell transcriptome data from a comprehensive set of 119 tumor samples from 15 cancer types and validate the predicted drug combination with literature evidence, mining clinical trial data, perturbation of patient-derived cell line data, and finally in-vivo samples.ConclusionsOverall, comboSC provides a feasible and one-stop computational prototype and a proof-of-concept study to predict potential drug combinations for further experimental validation and clinical usage using the single-cell transcriptome, which will facilitate and accelerate personalized tumor treatment by reducing screening time from a large drug combination space and saving valuable treatment time for individual patients. A user-friendly web server of comboSC for both clinical and research users is available at www.combosc.top. The source code is also available on GitHub at https://github.com/bm2-lab/comboSC.

Design of SAHA-Loaded PLGA Nanoparticles Aimed for Use in Breast Cancer Combination Therapy

Design of SAHA-Loaded PLGA Nanoparticles Aimed for Use in Breast Cancer Combination Therapy

Synergistic Effects of Tranylcypromine and NRF2 Inhibitor: A Repurposing Strategy for Effective Cancer Therapy.

Drug repurposing has emerged as an attractive strategy for accelerating drug discovery for cancer treatment. In this study, we investigated combining Tranylcypromine (TCP) with a number of well-characterized drugs. Among these combinations, NRF2 inhibitor (ML385) exhibited synergistic effects in combination with TCP. Specifically, our results showed that the combination of TCP and ML385 resulted in a significant reduction in tumor proliferation while neither drug affected cancer cell growth meaningfully on its own. While further studies are needed to understand fully the extent of the synergistic efficacy, the underlying respective mechanisms and the potential side effects of this approach, our study has yielded a promising start for the development of an effective combination cancer therapy.

Targosomes: Anti-HER2 PLGA nanocarriers for bioimaging, chemotherapy and local photothermal treatment of tumors and remote metastases

Developing combined cancer therapy strategies is of utmost importance as it can enhance treatment efficacy, overcome drug resistance, and ultimately improve patient outcomes by targeting multiple pathways and mechanisms involved in cancer growth and progression. Specifically, the potential of developing a combination chemo&photothermal therapy using targeted polymer nanoparticles as nanocarriers offers a promising approach for synergistic cancer treatment by combining the benefits of both therapies, such as targeted drug delivery and localized hyperthermia. Here, we report the first targeted anti-HER2 PLGA nanocarriers, called targosomes, that simultaneously possess photothermal, chemotherapeutic and diagnostic properties using only molecular payloads. Biocompatible poly(lactic-co-glycolic acid), PLGA, nanoparticles were loaded with photosensitizer phthalocyanine, diagnostic dye Nile Blue, and chemotherapeutic drug irinotecan, which was chosen as a result of screening a panel of theragnostic nanoparticles. The targeted delivery to cell surface oncomarker HER2 was ensured by nanoparticle modification with the anti-HER2 monoclonal antibody, trastuzumab, using the one-pot synthesis method without chemical conjugation. The irradiation tests revealed prominent photothermal properties of nanoparticles, namely heating by 35 °C in 10 min. Nanoparticles exhibited a 7-fold increase in binding and nearly an 18-fold increase in cytotoxicity for HER2-overexpressing cells compared to cells lacking HER2 expression. This enhancement of cytotoxicity was further amplified by >20-fold under NIR light irradiation. In vivo studies proved the efficacy of nanoparticles for bioimaging of primary tumor and metastasis sites and demonstrated 93% tumor growth inhibition, making these nanoparticles excellent candidates for translation into theragnostic applications.

The advancement of carrier-free nanodrug delivery system on cancer monotherapy and combination therapy

The advancement of carrier-free nanodrug delivery system on cancer monotherapy and combination therapy

One-pot synthesis of ultrasmall ferric ion coupled mitoxantrone nanoparticles for high bioavailability and effective chemo-ferroptosis combination therapy of breast cancer

Mitoxantrone (MIT) as a first line anticancer drug, is usually suffered from poor bioavailability upon in vivo application. Although previous studies have developed some carriers to improve its bioavailability, they also have the shortage of low drug loading and reproducibility. Herein, we proposed a facile one-pot method to synthesize ultrasmall ferric ion coupled mitoxantrone nanoparticles (Fe-MIT NPs) for effective therapy of breast cancer. The important finding includes: 1) The Fe-MIT NPs exhibited an average size of 40 nm with good dispersity and prolonged circulation in the bloodstream; 2) Fe-MIT NPs showed a high degree of accumulation within the tumor; 3) Fe-MIT NPs had a notable chemotherapy effect on cancer cells, which was achieved by increasing intracellular levels of reactive oxygen species (ROS); 4) The loaded Fe3+ within Fe-MIT NPs initiated ferroptosis through the Fenton reaction; 5) The ultrasmall size of the Fe-MIT NPs enabled better penetration of tumors. Therefore, when compared to free MIT, the Fe-MIT NPs delivered superior anticancer benefits. These benefits were observed in MCF-7 cells, MCF-7 multicellular tumor spheroids (MCTS), and MCF-7 tumor-bearing models.

Manganese Dioxide/Gold-based Active Tumor Targeting Nanoprobes for Enhancing Photodynamic and Low-Temperature-Photothermal Combination Therapy in Lung Cancer.

Tumor drug resistance caused by the tumor microenvironment is an extremely difficult problem for researchers to solve. Nanoplatforms that integrate diagnosis and treatment have great advantages in tumor treatment, but the design and synthesis of simple and efficient nanoplatforms still face tremendous challenges. In this study, a novel Mn/Au@ir820/GA-CD133 nanoprobe was developed. The manganese dioxide/gold particles were prepared by coprecipitation/assembly, chemically coupled with CD133 antibody, and finally loaded with the photosensitive drug IR820 and the heat shock protein inhibitor Ganetespib. The nanoprobe demonstrated good tumor-targeting ability, increased the level of singlet oxygen produced from laser irradiation by effectively alleviating tumor hypoxia, and decreased the threshold of heat tolerance by downregulating the expression of HSP90 in tumor tissues. This nanoprobe successfully inhibited the growth and progression of tumor tissues in a tumor-bearing mouse model by improving the effectiveness of photodynamic and low-temperature photothermal combination therapy.

Additivity predicts the efficacy of most approved combination therapies for advanced cancer.

Most advanced cancers are treated with drug combinations. Rational design aims to identify synergistic combinations, but existing synergy metrics apply to preclinical, not clinical data. Here we propose a model of drug additivity for progression-free survival (PFS) to assess whether clinical efficacies of approved drug combinations are additive or synergistic. This model includes patient-to-patient variability in best single-drug response plus the weaker drug per patient. Among US Food and Drug Administration approvals of drug combinations for advanced cancers (1995-2020), 95% exhibited additive or less than additive effects on PFS times. Among positive or negative phase 3 trials published between 2014-2018, every combination that improved PFS was expected to succeed by additivity (100% sensitivity) and most failures were expected to fail (78% specificity). This study shows synergy is neither a necessary nor common property of clinically effective drug combinations. The predictable efficacy of approved combinations suggests that additivity can be a design principle for combination therapies.

EXTH-41. COMBINATION TREATMENT OF CALCIUM CHANNEL ANTAGONIST MIBEFRADIL ENHANCES THE EFFECT OF HYDROXYUREA AT THERAPEUTIC RANGES IN HIGH-GRADE MENINGIOMA IN VITRO

Abstract High-grade meningiomas (MNs), WHO Grade II- III, are highly aggressive brain tumors that are difficult to treat. Standard chemotherapy agents are, at best, moderately effective in treating high-grade MNs. There is great interest in developing combinatorial drug treatment regimens to enhance the effects of standard chemotherapy. Many cancer types, including brain tumors, have an increase in the expression of voltage-gated calcium channels (VGCCs). These channels are involved in the regulation of cell cycle, proliferation, and apoptosis, among other functions. FDA-approved VGCC antagonists nimodipine (NIMO) and mibefradil (MIB) target two different VGCCs, L- and T-type channels, and have been of great interest for their use in combination therapy in other cancers. We sought to determine the efficacy of chemotherapy agents tested at clinically relevant concentrations for the treatment of high-grade MNs alone or in combination with NIMO or MIB. We cultured CH-157MN and IOMM-Lee MN cells and assessed their cell survival, apoptosis, and proliferation in the presence of temozolomide, octreotide, sunitinib, or hydroxyurea (HU). We confirmed that HU (150 µM) was the most efficacious chemotherapy agent, decreasing cell viability at therapeutic ranges. Monotherapy treatment with 2 or 4 µM MIB significantly decreased cell viability in both cell lines, whereas 1 µM NIMO only affected IOMM-Lee cells. The combination of HU and MIB further decreased cell viability but only in the most aggressive cell line, IOMM-Lee, whereas NIMO did not enhance HU’s ability to decrease cell survival. Remarkably, we detect an enhancement of HU’s effect by MIB when both agents are used within therapeutic ranges, as reported by pharmacokinetic studies. Here we demonstrate for the first time that T-type calcium channels play an important role in MN survival. The combination of HU and MIB suggests their use could be a promising treatment for high-grade MN.

Using anti-PD-L1 antibody conjugated gold nanoshelled poly (Lactic-co-glycolic acid) nanocapsules loaded with doxorubicin: A theranostic agent for ultrasound imaging and photothermal/chemo combination therapy of triple negative breast cancer.

Triple negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and it is difficult to progress through traditional chemotherapy. Therefore, the treatment of TNBC urgently requires agents with effective diagnostic and therapeutic capabilities. In this study, we obtained programmed death-ligand 1 (PD-L1) antibody conjugated gold nanoshelled poly(lactic-co-glycolic acid) (PLGA) nanocapsules (NCs) encapsulating doxorubicin (DOX) (DOX@PLGA@Au-PD-L1 NCs). PLGA NCs encapsulating DOX were prepared by a modified single-emulsion oil-in-water (O/W) solvent evaporation method, and gold nanoshells were formed on the surface by gold seed growth method, which were coupled with PD-L1 antibodies by carbodiimide method. The fabricated DOX@PLGA@Au-PD-L1 NCs exhibited promising contrast enhancement in vitro ultrasound imaging. Furthermore, DOX encapsulated in NCs displayed good pH-responsive and photo-triggered drug release properties. After irradiating 200 μg/mL NCs solution with a laser for 10 min, the solution temperature increased by nearly 23°C, indicating that the NCs had good photothermal conversion ability. The targeting experiments confirmed that the NCs had specific target binding ability to TNBC cells overexpressing PD-L1 molecules. Cell experiments exhibited that the agent significantly reduced the survival rate of TNBC cells through photochemotherapy combination therapy. As a multifunctional diagnostic agent, DOX@PLGA@Au-PD-L1 NCs could be used for ultrasound targeted contrast imaging and photochemotherapy combination therapy of TNBC cells, providing a promising idea for early diagnosis and treatment of TNBC.

A cascaded enzyme system based on the catalase-like activity of Ti3C2Tx MXene nanosheets for the efficient combination cancer therapy

Catalytic therapy with enzymes and nanozymes is a promising approach to cancer treatment. However, it often proves inadequate when used as a standalone treatment. This work presents the catalase (CAT)-like activity of Ti3C2Tx MXene, a kind of two-dimensional (2D) material with photothermal capability. Ti3C2Tx nanosheets were then used to load glucose oxidase (GOx) and the anticancer drug doxorubicin hydrochloride (DOX), and modified with polyethylene glycol (PEG) to obtain an enzyme cascade system, named Ti3C2Tx-GOx/DOX-PEG, for anticancer purposes. Ti3C2Tx-GOx/DOX-PEG exhibited a photothermal conversion efficiency of ∼28.7% at 808 nm, enabling its use for near-infrared light-based photothermal therapy (PTT). In addition, Ti3C2Tx could decompose H2O2 to O2 in cancer cells, thereby enhancing starvation therapy by sensitizing GOx. Furthermore, alleviation of hypoxia could sensitize the chemotherapy of DOX. The decomposition of glucose by GOx could also generate H2O2 for the production of O2 by Ti3C2Tx. Ultimately, the cycling of the enzyme cascade reaction could alleviate tumor hypoxia and enable enhanced chemo/starvation/photothermal combination therapy. The CAT-like behavior of Ti3C2Tx as well as various enzymatic reactions catalyzed by Ti3C2Tx-GOx/DOX-PEG were systematically investigated by intra- and extracellular experiments. Results from both in vitro and in vivo studies demonstrated the effective anticancer capability of Ti3C2Tx-GOx/DOX-PEG. This enzyme cascade system has the potential to enhance material utilization and reduce side effects, thus opening up new opportunities for designing efficient and safe anticancer systems.

CASP1 is a target for combination therapy in pancreatic cancer

Gemcitabine (GEM) is commonly used as the first-line chemotherapeutic agent for treating pancreatic cancer (PC) patients. However, drug resistance is a major hurdle in GEM-based chemotherapy for PC. Recent studies have shown that pyroptosis, a type of programmed death, plays a significant regulatory role in cancer development and therapy. In this study, we observed an increase in the expression of Caspase-1(CASP1)/Gasdermin-D (GSDMD) in PC and found that high expression of CASP1 and GSDMD was associated with poor overall survival (OS) and progression-free survival (PFS) of PC patients. Knockdown of either CASP1 or GSDMD resulted in the inhibition of cell viability and migration in PC cells. More importantly, the knockdown of CASP1 or GSDMD enhanced GEM-induced cell death in PC cells. Interestingly, subsequent investigations demonstrated that enzymatically active CASP1 promoted GEM-induced cell death in PC cells. The activation of CASP1 by the DPP8/DPP9 inhibitor (Val-boroPro, VbP) increased GEM-induced cell death by inducing pyroptosis. These findings suggest that inhibiting CASP1 to suppress its oncogenic effects or activating it to promote cell pyroptosis both enhance the sensitivity of PC cells to GEM therapy.

CRISPR Screening Identifies Mechanisms of Resistance to KRASG12C and SHP2 Inhibitor Combinations in Non-Small Cell Lung Cancer.

Identification of resistance mechanisms to KRASG12C/SHP2 coinhibition highlights the need for additional combination therapies for lung cancer beyond on-pathway combinations and offers the basis for development of more effective combination approaches. See related commentary by Johnson and Haigis, p. 4005.

Bacterial Structure‐Inspired Synthesis of Tumor‐Microenvironment‐Activated Artificial Enzyme toward Photothermal Enhanced Chemodynamic Cancer Therapy

AbstractBacteria therapy, using large sizes bacteria equipped with flagella, could easily penetrate the tumor tissue, exerting amazing effects. Inspired by this, carbon nanotubes‐assisted strategy, using CNTs to simulate the flagella of bacteria, is developed to improve the ability of vector to enter the cell. Via bionics, tumor microenvironment (TME) specific‐activated composite photothermal/Fenton enzyme (PZCo‐800) reacted selectively on the tumor sites was developed via direct pyrolysis of a Co‐Porphyrin‐based conjugated porous polymer (CMP) coated zeolitic‐imidazolate‐framework (ZIF‐8) hybrid. Carbonization caused the formation of flagella‐like CNTs, improving the ability of particles entering the cancer cells. PZCo‐800 utilized the acidic and hydrogen peroxide (H2O2) to initiate the Fenton‐like reaction (CDT), producing reactive oxygen species (ROS) to kill tumor cells. Additionally, under laser irradiation (638 nm), the heat generated by PZCo‐800 offered a prominent photothermal therapy (PTT) boosting the Fenton‐like therapeutic effect. Both in vitro and in vivo assays verified the PTT and CDT worked collaboratively with a remarkable inhabitation of 81.17 % on tumor growth, far outperforming the monomodal CDT and PTT. This microenvironment activated artificial enzyme enabled safe and reliable cancer combination therapy.

An Analysis of Risk Factors for the Development of Acneiform Eruptions in Patients on Monoclonal Antibody Epidermal Growth Factor Receptor Inhibitors

Acneiform eruptions occur frequently and early in patients on epidermal growth factor receptor inhibitors (EGFRi). Identification of baseline patient risk factors would prompt earlier referral to dermatology to optimize prevention and management. The primary objective of this retrospective study is to determine the association between clinical and demographic characteristics and the development of acneiform eruptions. A retrospective chart review was conducted on patients diagnosed with colon and head and neck cancers who started EGFRi between January 2017 and December 2021. Patients were followed until death or September 2022. Baseline demographic and clinical parameters were documented and patients were followed from the time of diagnosis to most recent visit for the development and management of an acneiform eruption. Regression analyses were performed to determine the association between baseline characteristics and the development of acneiform eruptions. A total of 66 patients were treated with cetuximab or panitumumab between 2017-2021 were included in the analysis. Forty-seven of the sixty-six patients developed an acneiform eruption while on EGFRi therapy (71.2%). Combination cancer therapy with another chemotherapeutic agent was associated with a lower risk of acneiform eruption (OR 0.03, P = .027). No other baseline features were statistically associated with a lower risk of acneiform eruption. Acneiform eruptions are a common cutaneous adverse event of EGFRi therapy. Ongoing research is required to elucidate risk factors for the development of acneiform eruptions, to improve the quality of life of oncology patients.

P50-5 Efficacy and safety of CBDCA/ETP/ICI combination therapy for extensive-stage small cell lung cancer in elderly patients

P50-5 Efficacy and safety of CBDCA/ETP/ICI combination therapy for extensive-stage small cell lung cancer in elderly patients

Polypyrrole nanoparticles loaded with doxorubicin for pH-responsive combinational photothermal-chemotherapy of cancer cells

The combined treatment method integrated photothermal therapy (PTT) with chemotherapy is extremely promising owing to the synergistic therapeutic effect as compared to single PTT or chemotherapy. To facilitate more novel and facile photothermal-chemotherapy drugs as well as promote controllable combination therapy, we have developed a mild and facile method to fabricate polymer polypyrrole (PPy)-doxorubicin (DOX) nanoparticles (NPs) as pH-responsive drug nanocarriers for synergistic photothermal-chemotherapy. In the nanoplatform, poly-L-lysine (PLL)-modified PPy serves as the photothermal material, and (DOX) molecules are adopted as the chemotherapy agent. Based on the cross-linking reaction of glutaraldehyde, DOX molecules are flexibly and efficiently assembled on the surface of PLL-modified PPy NPs. The obtained PPy-DOX NPs possess high photothermal effect, superior loading capacity of DOX, and controlled drug release behavior. The combination photothermal-chemotherapy based on PPy-DOX NPs has significantly enhanced the antitumor therapy effect. In general, the designed PPy-DOX NPs may be a potential drug delivery nanoplatform for cancer combination therapy.

A retrospective real-world study: the efficacy of immune-related combination therapies in advanced non-small cell lung cancer after resistance to EGFR-TKIs

BackgroundWhether patients with advanced non-small cell lung cancer (NSCLC) should choose an immune-combination therapy regimen after EGFR-tyrosine kinase inhibitors (EGFR-TKIs) resistance is currently unclear.MethodsWe evaluated 118 NSCLC patients treated by immune checkpoint inhibitors (ICIs) + chemotherapy (I + C), ICIs + chemotherapy + antiangiogenic therapy (I + C + A), chemotherapy + antiangiogenic therapy (C + A) after inefficacy of EGFR-TKIs. We assessed the objective remission rate (ORR), disease control rate (DCR), and progression-free survival (PFS) of these treatments.ResultsThe ORR was 26.1% vs 38.2% vs 16.3% in the three groups (P = 0.093). The divergence in DCR was also statistically significant (65.2% vs 85.3% vs 74.4%, P = 0.209). The median PFS was no statistically significant difference in PFS (3.09 vs 6.31 vs 5.91 months, P = 0.809), but the Kaplan–Meier survival curve of 12-month-PFS indicated an apparent survival advantage in the I + C + A group (P = 0.001). In addition, the I + C/I + C + A group showed higher median PFS than the C + A group in patients with brain metastases (median PFS, 6.44 vs 4.21 months, P = 0.022). The divergence in ORR of patients in the brain group was also statistically significant (P = 0.045). The I + C + A group showed superior efficacy in patients with liver metastases (median PFS, 0.95 vs 6.44 vs 3.48 months, P < 0.0001). The Cox proportional hazard modeling analysis suggested that the age, brain metastases, and liver metastases were all connected with the prognosis.ConclusionsThis study suggests that advanced NSCLC patients after resistance to EGFR-TKIs may achieve better outcomes from triple therapy. Patients with brain metastases favor ICIs-related combination therapies and patients with liver metastases prefer I + C + A therapy.

Prediction of the mechanism for the combination of diallyl trisulfide and cisplatin against gastric cancer: a network pharmacology study and pharmacological evaluation.

Background: In this research, we aimed to explore the efficacy of diallyl trisulfide (DATS) combined with cisplatin (DDP) for gastric cancer treatment and its underlying mechanism based on network pharmacology. Methods: First, the pharmacological mechanism by which DATS combined with DDP acts against gastric cancer was predicted using network pharmacology. The TTD, GeneCards, and OMIM databases were used to extract drug and disease targets. The David Bioinformatics Resources 6.8 database was used to conduct GO and KEGG analyses. We investigated the efficacy of DATS combined with DDP against gastric cancer in SGC7901 cells and a xenograft model. Furthermore, the specific mechanism of DATS combined with DDP, inferred by network pharmacology, was identified by Western blotting and immunohistochemistry. Results: The combination of DDP and DATS significantly increased cytotoxicity and cell apoptosis compared to the DATS or DDP treatment group in vitro. In addition, continuous intraperitoneal injection of DATS markedly improved the tumor inhibitory effect of DDP in the SGC-7901 tumor-bearing mouse model. Furthermore, network pharmacology and experimental validation studies revealed that the combination of DATS and DDP synergistically enhanced antitumor activity by regulating endoplasmic reticulum stress and inhibiting STAT3/PKC-δ and MAPK signaling pathways. Conclusion: Our study showed that the combination of DATS and DDP could exert outstanding therapeutic effects in gastric cancer. Moreover, network pharmacology coupled with experimental validation revealed the molecular mechanisms of combination therapy for gastric cancer. This study offers a new adjuvant strategy based on DATS and DDP for the treatment of gastric cancer.

Intra-arterial chemotherapy plus BCG, a promising combination adjuvant treatment for high-risk NMIBC

PurposeTo develop a novel combination therapy for high-risk nonmuscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT), namely, intra-arterial chemotherapy (IAC) plus BCG immunotherapy, and to compare the feasibility and safety of the 2 therapies. Materials and methodsA retrospective study was conducted on the data of 119 patients who were diagnosed with high-risk NMIBC and underwent TURBT in the past 5 years. Those who did not complete the treatment were excluded, and the remaining 98 patients were divided into 2 groups: both groups received intravesical BCG immunotherapy, while the BCG+IAC group received 4 courses of extra intra-arterial chemotherapy. Clinical and follow-up data were processed using statistical software. ResultsThe recurrence rate was 22.2% in the BCG+IAC group and 35.8% in the BCG group, whereas the progression rates were 8.9% and 24.5%, respectively. In the Kaplan-Meier plot, a statistically significant difference was observed with respect to recurrence-free survival (p = 0.025), as well as the progression-free survival of the two groups was similar (p = 0.019). A total of 22.2% of the patients with adverse effects of IAC and 79.6% of patients suffered from adverse reactions to BCG immunotherapy, and most of the adverse effects were mild and tolerable. Univariate and multivariate analysis indicated that multifocal and treatment were independent risk factors for recurrence, while the history of recurrence and treatment were independent risk factors for progression. ConclusionIAC could be a promising auxiliary treatment for BCG immunotherapy in decreasing the recurrence and progression rate of high-risk NMIBC with little additional toxicity.