Autoantibodies to tumor-associated antigens (TAAs) have been demonstrated as reporters in early carcinogenesis. Luminex technology enables the development of simultaneous detection of multiple autoantibodies. This study aimed to use Luminex technology to evaluate and develop an optimal panel for the detection of prostate cancer (PCa) based on autoantibodies to fourteen TAAs (p53, p16, IMP2, IMP3, SOX2, BIRC5, HIF1-α, HSP60, ENO1, CTAG1B, MUC1, Her2, GAL1, and GAL3) associated with cancers. A total of 163 samples including 91 PCa sera and 72 normal control sera were screened to evaluate the expression of fourteen autoantibodies by multiple autoantibody bead panel. Except for autoantibodies to Her2 and IMP3, twelve autoantibodies showed significantly high frequencies ranging from 19.8% to 51.6% in the PCa group at 95.8% specificity for normal controls. The area under the curve (AUC) of these twelve autoantibodies ranged from 0.609 to 0.868. After logistic regression modeling and leave-one-out cross-validation, an optimal panel with the combination of three autoantibodies to p16, IMP2, and HSP60 was developed, achieving an AUC of 0.909 with 71.4% sensitivity and 95.8% specificity. Autoantibody to HSP60 exhibiting the best performance with an AUC of 0.868 in the autoantibody bead panel was further validated by Enzyme-linked immunosorbent assay (ELISA) with a larger size sample containing 200 PCa sera and 137 normal control sera, it also showed an AUC of 0.848 to identify PCa from normal controls. Therefore, the autoantibody bead panel showed similar results to ELISA. In summary, we developed an optimal autoantibody bead-based panel for the detection of PCa. It could be used as a high throughput tool to facilitate Pca detection. Citation Format: Cuipeng Qiu, Xiao Wang, Serina Batson, Giulio Francia, Jian-Ying Zhang. Using Luminex approach to develop a panel of anti-TAA autoantibodies for the detection of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3328.
Among the main challenges for the treatment of breast cancers is disease spread which is often coupled with resistance to chemotherapy. Furthermore, patients with late stage breast cancer go through first- and second-line therapies before they are candidates for new and/or experimental therapies. At such late stages, tumors that might have responded to new therapies have evolved to express multi-drug resistance - conceivably as a consequence of exposure to the initial therapies. Many mechanisms have been proposed to contribute to drug resistance, ranging from (but not limited to) reduced drug penetration and the activity of drug efflux pumps through to cell-adhesion mediated resistance to cell death. To address these challenges we sought to determine whether; a) tumor metastasis to different secondary sites generates location-specific tumor phenotypes that alter sensitivity to chemotherapy and, b) whether pre-treatment of tumors to conventional paclitaxel (PTX) chemotherapy alters their sensitivity to new drugs. First, we implanted 2x10(5) human luciferase-positive LM2-4 human breast cancer cells intracardiacally into SCID mice (n=15), which resulted 2 weeks later in the development of widespread metastases to the lungs, liver, spleen, and bone. For some of the mice bearing such metastases, PTX therapy (20mg/kg, i.p.) was administered 24 hours before the mice were euthanized. Next, we used RNA sequencing of isolated LM2-4 metastatic nodules to determine the impact of the location of metastases on transcriptome profiles (assessed by 40 million reads per each total RNA sample, followed by Principal Component Analysis). This study revealed that lung metastases have similar signatures to metastases to spleen and ovary, and to metastases in those organs following PTX therapy, while such transcriptome profiles are all quite distinct from those of metastases of the same tumor to the liver. These changes presumably are due to different cell-cell interactions of tumor cells in the different organs, as well as a consequence of the different microenvironments. Second, we set up a drug screen of LM2-4 breast cancer cells recovering from 1nM paclitaxel 24hr exposure in vitro to test for drugs that are toxic to the tumor cells following PTX pre-exposure. A screen of 30,000 small molecule drugs thus far identified 7 hit compounds. Our results serve a proof of concept that the location of metastases can alter the tumor cell phenotype, as can pre-treatment with PTX, and suggest that in some cases therapy ought to be tailored to the location of metastasis. Based on those results we identified drugs that may be useful in hampering the tumor cell recovery from PTX chemotherapy. Our work serves as a test ground for stratifying tumors based on their tissue of tumor spread, and provide a rationale for identifying drugs that hamper recovery of tumor cells to chemotherapy agents often incorporated into first and second line therapies, such as paclitaxel. Citation Format: Joseph Wingate, Diana Gonzalez Garcia, Karla Parra, Serina Batson, Joel Martinez, Ivan Sosa Ontiveros, Renato Aguilera, Armando Varela, Paloma Valenzuela, Marcos Armendariz, Chloe Clifton, Arlene Levario, Angelica Chacon, Andres Villagrana, Emmanuel Sanchez, Guido Bocci, Giulio Francia. Paclitaxel directed screening to identify novel anti-cancer drugs [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2622.
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Metastatic breast cancer is a major cause of death for women in the US, and breast cancers that metastasize to the brain have a particularly poor prognosis. To treat brain metastases of Her-2 positive breast cancers a number of Her-2 targeting drugs are now clinically available, including lapatinib, neratinib and tucatinib, among others. However, in part as a consequence of poor penetration of many drugs into the brain, combinations of standard chemotherapy plus targeted agent have only modest impact on progression free survival for such patients. We have developed preclinical models of human Her-2 positive breast cancer brain metastases to help address these issues. We selected human MDA-MD-361 and BT474 breast cancer cells lines by in vivo passaging in SCID mice, followed by molecular tagging of the derived variants (MDA361R and BT474R respectively), and then the stereotactic implantation of such cells into the brain of female SCID mice. Using luciferase-tagged BT474R we implanted 75,000 cells into the brains of the mice, and thereafter confirmed by luminescence the growth of the cells, which allowed for randomization of the mice to receive control saline (n=7), metronomic gemcitabine (100mg/kg/3days; i.p.; n=8), neratinib (40mg/kg/3 days; p.o.; n=7), or the combination of gemcitabine plus neratinib (n=8), which continued for 5 months largely in the absence of overt toxicity. The gemcitabine plus neratinib combination prolonged survival over the controls (150 days vs 65 days, p<0.5), although eventually all mice succumbed to disease. Tumors cells have been isolated from these therapy-administered mice for further characterization. Neratinib alone did not result in an increase in survival compared to controls, whereas metronomic gemcitabine improved survival but was inferior to the combination. We confirmed these findings using MDA361R tagged with human chorionic gonadotropin (hCG), which allows for the growth of cells to be monitored by assessment of hCG in the mouse urine, and these cells were implanted intracranially into female SCID mice. After urine hCG levels confirmed the presence of growing cells in the brain, the mice were randomized to the above 4 therapies (n=4/group), which showed an increase in survival of the combination compared to controls. These results point to intriguing effects of chemotherapy when used at continuous low (metronomic) doses, that in these studies involved gemcitabine administration every 3 days, and which in these models can be effectively combined with neratinib to suppress the growth of Her-2 positive breast cancer cells implanted into the mouse brain. These results highlight promising combination that could be used to suppress Her-2 positive breast cancer brain metastatic growth, and the developed models should facilitate the study of this subset of breast cancers. Citation Format: Serina Batson, Alejandro Sanchez, Hector M. Padilla, Diana L. Prospero, Brenda Lugo, Valeria V. Lopez, Daniella E. Estrada, Nydia De Avila, Saeedeh Darvishi, Arlene Levario, Shan Man, Ping Xu, Robert S. Kerbel, Guido Bocci, Giulio Francia. Metronomic gemcitabine plus neratinib effectively inhibits the growth of human Her-2 positive breast cancer cells intracranially implanted into immunodeficient mice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3998.
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