The Center for Cancer Systems Pharmacology

Research

Breast & Ovarian Cancer

By understanding the biological mechanisms underlying breast and ovarian cancers, we aim to improve cancer diagnosis, interception, and treatment.

Nearly one-third of U.S. women will develop breast cancer in their lifetimes. While enhanced screening and treatment strategies have improved 5-year survival rates (to 91% overall [i]), breast cancer remains the second-leading cause of cancer-related death for women. Ovarian cancer accounts for far fewer new diagnoses per year (<1% of new cases) but is often diagnosed at late stages when the disease is difficult to treat. This results in a lower overall 5-year relative survival rate of 50.9%.[ii] In addition, people who inherit a mutated copy of the BRCA1 or BRCA2 genes are at an even greater risk of developing breast or ovarian cancer in their lifetimes.

At the LSP, we use several strategies to improve breast and ovarian cancer diagnosis and treatment. One approach uses deep tissue profiling to understand the molecular changes that underlie breast and ovarian cancer development, which can lead to improved biomarkers for diagnosis and treatment or strategies for intercepting and preventing cancer formation. Other efforts harness high-throughput systems pharmacology approaches to identify new therapeutic strategies for halting and eradicating tumors. 

LSP investigators Sandro Santagata and Peter Sorger serve as leaders for the Gray Foundation’s BRCA Precancer Atlas, which seeks to improve the prevention and treatment of cancers associated with BRCA1/2 mutation. We aim to understand the molecular changes that underlie breast and ovarian cancer and collaborate closely with clinicians to apply new molecular knowledge to improve clinical practice.

Related News

December 4, 2024
The LSP Welcomes Pathology Expert Sandro Santagata as New Associate Director
October 9, 2024
A Promising New Strategy for Treating Triple-Negative Breast Cancer

Featured Publications

Ovarian cancer-derived IL-4 promotes immunotherapy resistance

Mollaoglu and Tepper et al
Cell. 2024 Oct 25. PMID: 39481380
Journal
PubMed

Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma

Kader et al.
Cancer Discovery. 2025 May 5. PMID: 39704522.
Journal
PubMed

Related Publications

Ovarian Cancer

Mollaoglu, G., Tepper, A., Falcomatà, C., Potak, H. T., Pia, L., Amabile, A., Mateus-Tique, J., Rabinovich, N., Park, M. D., LaMarche, N. M., Brody, R., Browning, L., Lin, J.-R., Zamarin, D., Sorger, P. K., Santagata, S., Merad, M., Baccarini, A., & Brown, B. D. (2024). Ovarian cancer-derived IL-4 promotes immunotherapy resistance. Cell, 187(26), 7492-7510.e22. https://doi.org/10.1016/j.cell.2024.10.006
Kader, T., Lin, J.-R., Hug, C. B., Coy, S., Chen, Y.-A., de Bruijn, I., Shih, N., Jung, E., Pelletier, R. J., Lopez Leon, M., Mingo, G., Omran, D. K., Lee, J. S., Yapp, C., Satravada, B. A., Kundra, R., Xu, Y., Chan, S., Tefft, J. B., … Santagata, S. (2024). Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma. Cancer Discovery. https://doi.org/10.1158/2159-8290.CD-24-1366
Ding, L., Wang, Q., Martincuks, A., Kearns, M. J., Jiang, T., Lin, Z., Cheng, X., Qian, C., Xie, S., Kim, H.-J., Launonen, I.-M., Färkkilä, A., Roberts, T. M., Freeman, G. J., Liu, J. F., Konstantinopoulos, P. A., Matulonis, U., Yu, H., & Zhao, J. J. (2023). STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer. Journal for Immunotherapy of Cancer, 11(1), e005627. https://doi.org/10.1136/jitc-2022-005627
Launonen, I.-M., Lyytikäinen, N., Casado, J., Anttila, E. A., Szabó, A., Haltia, U.-M., Jacobson, C. A., Lin, J. R., Maliga, Z., Howitt, B. E., Strickland, K. C., Santagata, S., Elias, K., D’Andrea, A. D., Konstantinopoulos, P. A., Sorger, P. K., & Färkkilä, A. (2022). Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer. Nature Communications, 13(1), 835. https://doi.org/10.1038/s41467-022-28389-3
Palmer, A. C., Plana, D., Gao, H., Korn, J. M., Yang, G., Green, J., Zhang, X., Velazquez, R., McLaughlin, M. E., Ruddy, D. A., Kowal, C., Muszynski, J., Bullock, C., Rivera, S., Rakiec, D. P., Elliott, G., Fordjour, P., Meyer, R., Loo, A., … Sorger, P. K. (2020). A proof of concept for biomarker-guided targeted therapy against ovarian cancer based on patient-derived tumor xenografts. Cancer Research, 80(19), 4278–4287. https://doi.org/10.1158/0008-5472.CAN-19-3850
Izar, B., Tirosh, I., Stover, E. H., Wakiro, I., Cuoco, M. S., Alter, I., Rodman, C., Leeson, R., Su, M.-J., Shah, P., Iwanicki, M., Walker, S. R., Kanodia, A., Melms, J. C., Mei, S., Lin, J.-R., Porter, C. B. M., Slyper, M., Waldman, J., … Regev, A. (2020). A single-cell landscape of high-grade serous ovarian cancer. Nature Medicine, 26(8), 1271–1279. https://doi.org/10.1038/s41591-020-0926-0
Färkkilä, A., Gulhan, D. C., Casado, J., Jacobson, C. A., Nguyen, H., Kochupurakkal, B., Maliga, Z., Yapp, C., Chen, Y.-A., Schapiro, D., Zhou, Y., Graham, J. R., Dezube, B. J., Munster, P., Santagata, S., Garcia, E., Rodig, S., Lako, A., Chowdhury, D., … Konstantinopoulos, P. A. (2020). Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer. Nature Communications, 11(1), 1459. https://doi.org/10.1038/s41467-020-15315-8

Breast Cancer

Girnius, N., Henstridge, A. Z., Marks, B., Yu, J. K., Gray, G. K., Sander, C., Zervantonakis, I. K., & Luna, A. (2024). Cilengitide sensitivity is predicted by overall integrin expression in breast cancer. Breast Cancer Research: BCR, 26(1), 187. https://doi.org/10.1186/s13058-024-01942-2
Schade, A. E., Perurena, N., Yang, Y., Rodriguez, C. L., Krishnan, A., Gardner, A., Loi, P., Xu, Y., Nguyen, V. T. M., Mastellone, G. M., Pilla, N. F., Watanabe, M., Ota, K., Davis, R. A., Mattioli, K., Xiang, D., Zoeller, J. J., Lin, J.-R., Morganti, S., … Cichowski, K. (2024). AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution. Nature, 635(8039), 755–763. https://doi.org/10.1038/s41586-024-08031-6
Conger, K. O., Chidley, C., Ozgurses, M. E., Zhao, H., Kim, Y., Semina, S. E., Burns, P., Rawat, V., Lietuvninkas, L., Sheldon, R., Ben-Sahra, I., Frasor, J., Sorger, P. K., DeNicola, G. M., & Coloff, J. L. (2024). ASCT2 is a major contributor to serine uptake in cancer cells. Cell Reports, 43(8), 114552. https://doi.org/10.1016/j.celrep.2024.114552
Guerriero, J. L., Lin, J.-R., Pastorello, R. G., Du, Z., Chen, Y.-A., Townsend, M. G., Shimada, K., Hughes, M. E., Ren, S., Tayob, N., Zheng, K., Mei, S., Patterson, A., Taneja, K. L., Metzger, O., Tolaney, S. M., Lin, N. U., Dillon, D. A., Schnitt, S. J., … Santagata, S. (2024). Qualification of a multiplexed tissue imaging assay and detection of novel patterns of HER2 heterogeneity in breast cancer. NPJ Breast Cancer, 10(1), 2. https://doi.org/10.1038/s41523-023-00605-3
Hermida-Prado, F., Xie, Y., Sherman, S., Nagy, Z., Russo, D., Akhshi, T., Chu, Z., Feit, A., Campisi, M., Chen, M., Nardone, A., Guarducci, C., Lim, K., Font-Tello, A., Lee, I., García-Pedrero, J., Cañadas, I., Agudo, J., Huang, Y., … Jeselsohn, R. (2023). Endocrine therapy synergizes with SMAC mimetics to potentiate antigen presentation and tumor regression in hormone receptor-positive breast cancer. Cancer Research, 83(19), 3284–3304. https://doi.org/10.1158/0008-5472.CAN-23-1711
Kalocsay, M., Berberich, M. J., Everley, R. A., Nariya, M. K., Chung, M., Gaudio, B., Victor, C., Bradshaw, G. A., Eisert, R. J., Hafner, M., Sorger, P. K., Mills, C. E., & Subramanian, K. (2023). Proteomic profiling across breast cancer cell lines and models. Scientific Data, 10(1), 514. https://doi.org/10.1038/s41597-023-02355-0
Mills, C. E., Subramanian, K., Hafner, M., Niepel, M., Gerosa, L., Chung, M., Victor, C., Gaudio, B., Yapp, C., Nirmal, A. J., Clark, N., & Sorger, P. K. (2022). Multiplexed and reproducible high content screening of live and fixed cells using Dye Drop. Nature Communications, 13(1), 6918. https://doi.org/10.1038/s41467-022-34536-7
Gray, G. K., Li, C. M.-C., Rosenbluth, J. M., Selfors, L. M., Girnius, N., Lin, J.-R., Schackmann, R. C. J., Goh, W. L., Moore, K., Shapiro, H. K., Mei, S., D’Andrea, K., Nathanson, K. L., Sorger, P. K., Santagata, S., Regev, A., Garber, J. E., Dillon, D. A., & Brugge, J. S. (2022). A human breast atlas integrating single-cell proteomics and transcriptomics. Developmental Cell, 57(11), 1400-1420.e7. https://doi.org/10.1016/j.devcel.2022.05.003
Wang, Q., Bergholz, J. S., Ding, L., Lin, Z., Kabraji, S. K., Hughes, M. E., He, X., Xie, S., Jiang, T., Wang, W., Zoeller, J. J., Kim, H.-J., Roberts, T. M., Konstantinopoulos, P. A., Matulonis, U. A., Dillon, D. A., Winer, E. P., Lin, N. U., & Zhao, J. J. (2022). STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer. Nature Communications, 13(1), 3022. https://doi.org/10.1038/s41467-022-30568-1
Keenan, T. E., Li, T., Vallius, T., Guerriero, J. L., Tayob, N., Kochupurakkal, B., Davis, J., Pastorello, R., Tahara, R. K., Anderson, L., Conway, J., He, M. X., Shannon, E., Godin, R. E., Sorger, P. K., D’Andrea, A., Overmoyer, B., Winer, E. P., Mittendorf, E. A., … Tolaney, S. M. (2021). Clinical efficacy and molecular response correlates of the WEE1 inhibitor adavosertib combined with cisplatin in patients with metastatic triple-negative breast cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 27(4), 983–991. https://doi.org/10.1158/1078-0432.CCR-20-3089
Mehta, A. K., Cheney, E. M., Hartl, C. A., Pantelidou, C., Oliwa, M., Castrillon, J. A., Lin, J.-R., Hurst, K. E., de Oliveira Taveira, M., Johnson, N. T., Oldham, W. M., Kalocsay, M., Berberich, M. J., Boswell, S. A., Kothari, A., Johnson, S., Dillon, D. A., Lipschitz, M., Rodig, S., … Guerriero, J. L. (2021). Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nature Cancer, 2(1), 66–82. https://doi.org/10.1038/s43018-020-00148-7
Bhola, P. D., Ahmed, E., Guerriero, J. L., Sicinska, E., Su, E., Lavrova, E., Ni, J., Chipashvili, O., Hagan, T., Pioso, M. S., McQueeney, K., Ng, K., Aguirre, A. J., Cleary, J. M., Cocozziello, D., Sotayo, A., Ryan, J., Zhao, J. J., & Letai, A. (2020). High-throughput dynamic BH3 profiling may quickly and accurately predict effective therapies in solid tumors. Science Signaling, 13(636). https://doi.org/10.1126/scisignal.aay1451
Chopra, S. S., Jenney, A., Palmer, A., Niepel, M., Chung, M., Mills, C., Sivakumaren, S. C., Liu, Q., Chen, J.-Y., Yapp, C., Asara, J. M., Gray, N. S., & Sorger, P. K. (2020). Torin2 exploits replication and checkpoint vulnerabilities to cause death of PI3K-activated triple-negative breast cancer cells. Cell Systems, 10(1), 66-81.e11. https://doi.org/10.1016/j.cels.2019.11.001
Hafner, M., Mills, C. E., Subramanian, K., Chen, C., Chung, M., Boswell, S. A., Everley, R. A., Liu, C., Walmsley, C. S., Juric, D., & Sorger, P. K. (2019). Multiomics profiling establishes the polypharmacology of FDA-approved CDK4/6 inhibitors and the potential for differential clinical activity. Cell Chemical Biology, 26(8), 1067-1080.e8. https://doi.org/10.1016/j.chembiol.2019.05.005

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