maytansine and Triple-Negative-Breast-Neoplasms

The field of medical oncology is experiencing a period of rapid evolution owing to advances in the fields of genomics, tumor biology, and immunology. These disciplines have provided valuable insights into the heterogeneity between breast tumors, key oncogenic drivers, and the role of the immune system in the natural history of breast cancer. This knowledge is translating into many novel therapeutic strategies using personalized medicines, targeted drug delivery systems, and immunomodulatory agents in the treatment of both the early and metastatic stages of the disease. This review article attempts to cover the major developments in experimental therapeutics and how they relate to our understanding of breast cancer and its various biologic subtypes.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Delivery Systems; Female; Humans; Immunotherapy; Ipilimumab; Maytansine; Molecular Targeted Therapy; Nivolumab; Poly(ADP-ribose) Polymerase Inhibitors; Precision Medicine; Protein Kinase Inhibitors; Receptor, ErbB-2; Receptors, Estrogen; Selective Estrogen Receptor Modulators; TOR Serine-Threonine Kinases; Trastuzumab; Triple Negative Breast Neoplasms

Folate receptor alpha (FRα) has been reported to be expressed in up to 80% of triple-negative breast cancers (TNBC) with limited expression in normal tissues, making it a promising therapeutic target. Mirvetuximab soravtansine (mirvetuximab-s) is an antibody drug conjugate which has shown promise in the treatment of FRα-positive solid tumors in early phase clinical trials. Herein, are the results of the first prospective phase II trial evaluating mirvetuximab-s in metastatic TNBC. Patients with advanced, FRα-positive TNBC were enrolled on this study. Mirvetuximab-s was administered at a dose of 6.0 mg/kg every 3 weeks. 96 patients with advanced TNBC consented for screening. FRα staining was performed on tumor tissue obtained from 80 patients. The rate of FRα positivity by immunohistochemistry was 10.0% (8/80). Two patients were treated on study, with best overall responses of stable disease in one and progressive disease in the other. Adverse events were consistent with earlier studies. The study was terminated early due to the low rate of FRα positivity in the screened patient population and lack of disease response in the two patients treated. The observed rate of FRα positivity was considerably lower than previously reported and none of the patients had a partial or complete response. Treatment with mirvetuximab-s should only be further explored in TNBC if an alternate biomarker strategy is developed for patient selection on the basis of additional preclinical data.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Female; Folate Receptor 1; Humans; Immunoconjugates; Maytansine; Prospective Studies; Triple Negative Breast Neoplasms

Triple-negative breast cancers (TNBCs) are highly aggressive and metastatic. To date, finding efficacious targeted therapy molecules might be the only window of hope to cure cancer. Fibromodulin (FMOD), is ectopically highly expressed on the surface of Chronic Lymphocytic Leukemia (CLL) and bladder carcinoma cells; thus, it could be a promising molecule for targeted therapy of cancer. The objective of this study was to evaluate cell surface expression of FMOD in two TNBC cell lines and develop an antibody-drug conjugate (ADC) to target FMOD positive TNBC in vitro and in vivo.. Two TNBC-derived cell lines 4T1 and MDA-MB-231 were used in this study. The specific binding of anti-FMOD monoclonal antibody (mAb) was evaluated by flow cytometry and its internalization was verified using phAb amine reactive dye. A microtubulin inhibitor Mertansine (DM1) was used for conjugation to anti-FMOD mAb. The binding efficacy of FMOD-ADC was assessed by immunocytochemistry technique. The anti-FMOD mAb and FMOD-ADC apoptosis induction were measured using Annexin V-FITC and flow cytometry. Tumor growth inhibition of anti-FMOD mAb and FMOD-ADC was evaluated using BALB/c mice injected with 4T1 cells.. Our results indicate that both anti-FMOD mAb and FMOD-ADC recognize cell surface FMOD molecules. FMOD-ADC could induce apoptosis in 4T1 and MDA-MB-231 cells in vitro. In vivo tumor growth inhibition was observed using FMOD-ADC in 4T1 inoculated BALB/c mice.. Our results suggests high cell surface FMOD expression could be a novel bio-marker TNBCs. Furthermore, FMOD-ADC could be a promising candidate for targeting TNBCs.

Topics: Amines; Animals; Antibodies, Monoclonal; Cell Line, Tumor; Disease Models, Animal; Fibromodulin; Humans; Immunoconjugates; Maytansine; Mice; Triple Negative Breast Neoplasms

Topics: Animals; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; Humans; Immunoconjugates; Lung Neoplasms; Maytansine; Mice; Mice, Nude; Trastuzumab; Triple Negative Breast Neoplasms

Metastatic triple-negative breast cancer is one of the most devastating cancer types. Systemic chemotherapy is necessary, but its clinical performance is largely limited by severe side effects. Herein, we report a mertansine prodrug, which could self-assemble into spherical nanoparticles in water and readily convert into active mertansine at the presence of glutathione. The self-assembling mertansine prodrugs (SAMPDs) entered cancer cells via a caveolae-mediated pathway and exhibited potent cytotoxicity. The self-delivering SAMPDs did not cause hemolysis, and more importantly increased maximum tolerated dose (MTD) of mertansine by 8 folds via reducing free mertansine exposure in most of the major organs. SAMPDs improved intratumoral drug exposure and showed dose-dependent antitumor activity. When dosed at MTD, SAMPDs inhibited primary tumor growth and pulmonary metastasis by 80% and 95%, while mertansine dosed at MTD only reduced primary tumor growth and metastasis by <50% and 60%, respectively. Our results reveal the mechanism of in vivo biotransformation of self-assembling prodrug and highlight the unique advantages of self-assembling prodrug strategy in improving the efficacy and safety of chemotherapy.

Topics: Antineoplastic Agents; Cell Line, Tumor; Humans; Maximum Tolerated Dose; Maytansine; Prodrugs; Triple Negative Breast Neoplasms

The goal of this study was to identify a novel target for antibody-drug conjugate (ADC) development in triple negative breast cancer (TNBC), which has limited treatment options, using gene expression datasets and in vitro siRNA/CRISPR and in vivo functional assays. We analyzed 4467 breast cancers and identified GABRP as top expressed gene in TNBC with low expression in most normal tissues. GABRP protein was localized to cell membrane with broad range of receptors/cell (815-53,714) and expressed by nearly half of breast cancers tissues. GABRP gene knockdown inhibited TNBC cell growth and colony formation in vitro and growth of MDA-MB-468 xenografts in nude mice. Commercially available anti-GABRP antibody (5-100 μg/ml) or de novo generated Fabs (20 μg/ml) inhibited TNBC cell growth in vitro. The same antibody conjugated to mertansine (DM1) also showed significant anticancer activity at nanomolar concentrations. Our results indicate that GABRP is a potential novel therapeutic target for ADC development.

Topics: Animals; Antineoplastic Agents; Breast; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Datasets as Topic; Drug Development; Female; GABA-A Receptor Antagonists; Gene Expression Profiling; Gene Knockdown Techniques; Humans; Immunoconjugates; Immunoglobulin Fab Fragments; Maytansine; Mice; Molecular Targeted Therapy; Receptors, GABA-A; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Triple-negative breast cancer (TNBC) is related with a poor prognosis as patients do hardly benefit from approved therapies. CD138 (Syndecan-1) is upregulated on human breast cancers. Indatuximab ravtansine (BT062) is an antibody-drug-conjugate that specifically targets CD138-expressing cells and has previously shown clinical activity in multiple myeloma. Here we show indatuximab ravtansine as a potential mono- and combination therapy for TNBC.. The effects of indatuximab ravtansine were assessed in vitro in SK-BR-3 and T47D breast cancer cell lines. The in vivo effects of indatuximab ravtansine alone and in combination with docetaxel or paclitaxel were assessed in MAXF401, MAXF1384 and MAXF1322 xenograft TNBC models.. These data demonstrate potential use of indatuximab ravtansine in combination with docetaxel or paclitaxel for CD138-positive TNBC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast; Cell Line, Tumor; Docetaxel; Female; Humans; Immunoconjugates; Maytansine; Mice; Mice, Nude; Paclitaxel; Syndecan-1; Treatment Outcome; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Doxorubicin; Female; Humans; Integrin alphaVbeta3; Maytansine; Mice, Nude; Micelles; Molecular Targeted Therapy; Oligopeptides; Prodrugs; Tissue Distribution; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays