Molecular Cancer Therapeutics

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ISSN / EISSN : 1535-7163 / 1538-8514
Total articles ≅ 5,490
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Vinodh Kannappan, Ying Liu, Zhipeng Wang, Karim Azar, Sathishkumar Kurusamy, Rajagopal S. Kilari, , Mark R. Morris, , Peng Liu, et al.
Molecular Cancer Therapeutics; https://doi.org/10.1158/1535-7163.mct-22-0066

Abstract:
Glioblastoma stem cell (GSC) is the major cause of glioblastoma multiforme (GBM) chemotherapy failure. Hypoxia is one of the determinants of GSC. NFκB plays a pivotal link between hypoxia and cancer stem cells (CSCs). Disulfiram (DS), an antialcoholism drug, has very strong NFκB-inhibiting and anti-CSC activity. In this study, the in vitro anti-GSC activity of DS and in vivo anti-GBM efficacy of poly lactic-co-glycolic acid nanoparticle-encapsulated DS (DS-PLGA) were examined. We attempt to elucidate the molecular network between hypoxia and GSCs, and also examined the anti-GSC activity of DS in vitro and in vivo. The influence of GSCs and hypoxia on GBM chemoresistance and invasiveness was studied in hypoxic and spheroid cultures. The molecular regulatory roles of NFκB, HIF1α and HIF2α were investigated using stably transfected U373MG cell lines. The hypoxia in neurospheres determines the cancer stem cell characters of the sphere-cultured GBM cell lines (U87MG, U251MG, U373MG). NFκB is located at a higher hierarchical position than HIF1α/HIF2α in hypoxic regulatory network and plays a key role in hypoxia-induced GSC characters. DS inhibits NFκB activity and targets hypoxia-induced GSCs. It showed selective toxicity to GBM cells, eradicates GSC and blocks migration and invasion at very low concentrations. DS-PLGA efficaciously inhibits orthotopic and subcutaneous U87MG xenograft in mouse models with no toxicity to vital organs.
Xinxing Pan, Zhe Geng, , Xingxing Li, Mi Zhang, Xusu Wang, Yu Cong, Ke Huang, Juan Xu,
Molecular Cancer Therapeutics; https://doi.org/10.1158/1535-7163.mct-21-0848

Abstract:
The lives of ovarian cancer patients are threatened largely due to metastasis and drug resistance. Endogenous peptides attract increasing attention in oncologic therapeutic area, a few anti-tumor peptides have been approved by the food and drug administration (FDA) for clinical use over the past decades. However, only few peptides or peptide-derived drugs with anti-ovarian cancer effects have been identified. Here we focused on the biological roles and mechanism of a peptide named PDHPS1 in ovarian cancer development. Our results indicated that PDHPS1 reduced the proliferation ability of ovarian cancer cells in vitro and inhibited the ovarian cancer growth in vivo. Peptide pull down and following mass spectrometry, western blot and qRT-PCR revealed that PDHPS1 could bind to protein phosphatase 2 phosphatase activator (PTPA), an essential activator of protein phosphatase 2A (PP2A), which resulted in increase of phosphorylated YAP, further inactivated YAP and suppressed the expression of its downstream target genes. Flow cytometry, cell membrane permeability test and immunohistochemical staining study demonstrated that there are no observable side effects of PDHPS1 on normal ovarian epithelium and hepatorenal function. Besides, modification of membrane penetration could improve the physicochemical properties and biological activity of PDHPS1. In conclusion, our study demonstrated that the endogenous peptide PDHPS1 serves as an anti-tumor peptide to inhibit YAP signaling pathway though interacting with PTPA in ovarian cancer.
Molecular Cancer Therapeutics; https://doi.org/10.1158/1535-7163.mct-21-0831

Abstract:
Not all genomic mutations are expressed at the transcript/protein level, which may explain variation in cancer development, prognosis, and treatment response/resistance. In this study, our aim was to describe the prevalence of somatic mutation loss of expression ('variant silencing') in a large collection of human samples, and the potential impact of such variant silencing on tumor immunogenicity. Whole-exome mutation description and tumor-normal paired mRNA expression data originating from 636 unique patients diagnosed with 21 distinct tumor types (all solid tumors) were retrieved from The Cancer Genome Atlas (TCGA). Antigenicity and immunogenicity of neo-peptides originating from mutated proteins within a same tumor sample were predicted using the tools available from the Immune Epitope Database (IEDB). A total of 65,072 missense mutations were studied. We demonstrated that 9.06% (N=10,604 silenced/117,505 total variants) somatic variants were silenced in human tumors. Transciptomic silencing is significantly associated with proteins presenting better peptide processing, MHC-I binding, and T-cell recognition; and is more likely observed in lymphocyte-depleted tumors. Silencing may participate in tumor resistance by clonal selection and immune evasion. In the era of precision medicine, we suggest that therapeutic choices should be informed by both the presence of a genomic mutation and its actual transcript expression.
Molecular Cancer Therapeutics; https://doi.org/10.1158/1535-7163.mct-22-0087

Abstract:
Although radiologic imaging and histological assessment of tumor tissues are classic approaches for diagnosis and monitoring of treatment response, they have many limitations. These include challenges in distinguishing benign from malignant masses, difficult access to the tumor, high cost of the procedures, and tumor heterogeneity. In this setting, liquid biopsy has emerged as a potential alternative for both diagnostic and monitoring purposes. The approaches to liquid biopsy include cell-free DNA/circulating tumor DNA (cfDNA/ctDNA), long and micro non-coding RNAs, proteins/peptides, carbohydrates/lectins, lipids, and metabolites. Other approaches include detection and analysis of circulating tumor cells (CTCs), extracellular vesicles (EVs), and tumor-activated platelets. Ultimately, reliable use of liquid biopsies requires bioinformatics and statistical integration of multiple data sets in order to achieve approval in a Clinical Laboratory Improvement Amendments (CLIA) setting. This review provides a balanced and critical assessment of recent discoveries regarding tumor-derived biomarkers in liquid biopsies along with the potential and pitfalls for cancer detection and longitudinal monitoring
Olivier Cabaud, Ludovic G. M. Berger, , José Adélaide, , Séverine Garnier, , Nadine Carbuccia, Anne Farina, Emilie Agavnian, et al.
Molecular Cancer Therapeutics; https://doi.org/10.1158/1535-7163.mct-22-0013

Abstract:
Antibody-drug conjugates (ADCs) represent a fast-growing drug class in oncology. However, ADCs are associated with resistance, and therapies able to overcome it are of utmost importance. Recently, enfortumab vedotin-ejfv (EV) was approved in nectin-4+ metastatic urothelial cancer. We previously described PVRL4/nectin-4, as a new therapeutic target in breast cancer (BC), and produced an efficient EV-like ADC comprising a human anti-nectin-4 monoclonal antibody conjugated to monomethyl auristatin-E (MMAE) named N41mab-vcMMAE. To study the consequence of the long-term treatment with this ADC, we developed a preclinical BC model in mice, and report a mechanism of resistance to N41mab-vcMMAE after a 9- months treatment and a way to reverse it. RNA-sequencing pointed to an upregulation in resistant tumors of ABCB1 expression, encoding the multidrug resistance protein MDR-1/P-glycoprotein (P-gp), associated with focal gene amplification and high protein expression. Sensitivity to N41mab-vcMMAE of the resistant model was restored in vitro by P-gp pharmacological inhibitors, like tariquidar. P-gp is expressed in a variety of normal tissues. By delivering the drug to the tumor more specifically than does classical chemotherapy, we hypothesized that the combined use of ADC with P-gp inhibitors might reverse resistance in vivo without toxicity. Indeed, we showed that the tariquidar/N41mab-vcMMAE combination was well tolerated and induced a rapid regression of ADC-resistant tumors in mice. By contrast, the tariquidar/docetaxel combination was toxic and poorly efficient. These results show that ABC transporter inhibitors can be safely used with ADC to reverse ADC-induced resistance and open new opportunities in the fight against multidrug resistance.
Juniper A. Scribner, Stuart W. Hicks, Kerstin W. Sinkevicius, Nicholas C. Yoder, Gundo Diedrich, Jennifer G. Brown, Jacquelynn Lucas, Megan E. Fuller, Thomas Son, Anahita Dastur, et al.
Molecular Cancer Therapeutics; https://doi.org/10.1158/1535-7163.mct-21-0915

Abstract:
A disintegrin and metalloprotease (ADAM) 9 is a member of the ADAM family of multifunctional, multidomain type 1 transmembrane proteins. ADAM9 is overexpressed in many cancers, including non-small cell lung, pancreatic, gastric, breast, ovarian, and colorectal cancer, but exhibits limited expression in normal tissues. A target-unbiased discovery platform based on intact tumor and progenitor cell immunizations, followed by an immunohistochemistry screen, led to the identification of anti-ADAM9 antibodies with selective tumor-versus-normal tissue binding. Subsequent analysis revealed anti-ADAM9 antibodies were efficiently internalized and processed by tumor cells making ADAM9 an attractive target for antibody-drug conjugate development. Here, we describe the preclinical evaluation of IMGC936, a novel antibody-drug conjugate targeted against ADAM9. IMGC936 is comprised of a high-affinity humanized antibody site-specifically conjugated to DM21-C, a next-generation linker-payload that combines a maytansinoid microtubule-disrupting payload with a stable tripeptide linker, at a drug antibody ratio of approximately 2.0. Additionally, the YTE mutation (M252Y/S254T/T256E) was introduced into the CH2 domain of the antibody Fc to maximize in vivo plasma half-life and exposure. IMGC936 exhibited cytotoxicity toward ADAM9-positive human tumor cell lines, as well as bystander killing, potent antitumor activity in human cell line-derived xenograft and patient-derived xenograft tumor models, and an acceptable safety profile in cynomolgus monkeys with favorable pharmacokinetic properties. Our preclinical data provide a strong scientific rationale for the further development of IMGC936 as a therapeutic candidate for the treatment of ADAM9-positive cancers. A first-in-human study of IMGC936 in patients with advanced solid tumors has been initiated (NCT04622774).
, Edgar Creus-Bachiller, Xiaohu Zhang, Maria Martínez-Iniesta, Sara Ortega-Bertran, , , Margaret R. Wallace, Cleofe Romagosa, Lourdes Salazar-Huayna, et al.
Molecular Cancer Therapeutics; https://doi.org/10.1158/1535-7163.mct-21-0947

Abstract:
Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas that are the leading cause of mortality in Neurofibromatosis type 1 (NF1) patients. Single chemotherapeutic agents have shown response rates ranging from 18-44% in clinical trials, so there is still a high medical need to identify chemotherapeutic combination treatments that improve clinical prognosis and outcome. We screened a collection of compounds from the NCATS Mechanism Interrogation PlatE (MIPE) library in three MPNST cell lines, using cell viability and apoptosis assays. We then tested whether compounds that were active as single agents were synergistic when screened as pairwise combinations. Synergistic combinations in vitro were further evaluated in patient-derived orthotopic xenograft (orthoxenograft/PDOX) athymic models engrafted with primary MPNST matching with their paired primary-derived cell line where synergism was observed. The high-throughput screening identified 21 synergistic combinations, from which four exhibited potent synergies in a broad panel of MPNST cell lines. One of the combinations, MK-1775 with Doxorubicin, significantly reduced tumor growth in a sporadic PDOX model (MPNST-SP-01) (sevenfold) and in an NF1-PDOX model (MPNST-NF1-09) (fourfold) and presented greater effects in TP53 mutated MPNST cell lines. The other three combinations, all involving Panobinostat (combined with NVP-BGT226, Torin 2, or Carfilzomib), did not reduce the tumor volume in vivo at non-cytotoxic doses. Our results support the utility of our screening platform of in vitro and in vivo models to explore new therapeutic approaches for MPNSTs and identified that combination MK-1775 with Doxorubicin could be a good pharmacological option for the treatment of these tumors.
Correction
Fei-Meng Zheng, Zi-Jie Long, Zhi-Jie Hou, Yu Luo, Ling-Zhi Xu, Jiang-Long Xia, Xiao-Ju Lai, Ji-Wei Liu, Xi Wang, Muhammad Kamran, et al.
Molecular Cancer Therapeutics, Volume 21, pp 856-856; https://doi.org/10.1158/1535-7163.mct-22-0150

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