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Principal Investigator: KORNELIA POLYAK
Organization: DANA-FARBER CANCER INST
Fiscal Year: 2024
Award: $1,007,771
Funding agency: National Cancer Institute
PROJECT SUMMARY:
Breast cancer is the most common cancer and the leading cause of cancer deaths in women world-
wide. While targeted and immune therapies have improved patient outcomes, a significant fraction of
patients fail to respond to treatment and die of their disease. Most of these therapeutic failures are
due to extensive intratumor heterogeneity (ITH) driven by genetic and epigenetic heterogeneity of
cancer cells in combination with selection forces of the local and systemic environment, such as
immune cells.
The focus of my laboratory is to understand breast tumor evolution using interdisciplinary
approaches and improve the clinical management of breast cancer patients based on this knowledge.
We have been at the forefront of studies analyzing tumors as a whole and emphasizing the
importance of both cancer cell and stromal heterogeneity in disease progression and therapeutic
resistance.
In our recent work, we made advances in dissecting the clinical and functional relevance of ITH.
We analyzed cellular genetic ITH in HER2+ breast cancer in relation to therapeutic responses. We
identified epigenetic enzymes as regulators of transcriptional heterogeneity and linked this to
treatment resistance. We showed that polyclonal tumors drive polyclonal metastases by altering the
local and systemic immune environments and we described progressively suppressive immune milieu
during breast tumor progression.
Our proposed research will focus on three general areas:
1. Decipher the breast tumor ecosystem at the single cell level: we will assess ITH using genomic
and computational tools to identify key cellular and spatial features of disease progression. We will
focus on preinvasive to invasive transition and treatment-resistant tumors progressing to metastatic
disease.
2. Conduct functional studies to gain mechanistic insights underlying ITH: we will apply single cell
tracking and functional screens in experimental models to assess the impact of metabolic and
microenvironmental stressors on ITH, especially epigenetic heterogeneity.
3. Design and test novel therapeutic approaches for heterogeneous breast tumors: we will follow up
known and new targets and conduct large-scale screens to identify synthetic lethal interactions and
understand mechanisms of synergy.
Our recent findings also highlight the importance of tumor-host interactions that go beyond the
tumor microenvironment. Even localized tumors have systemic effects and host factors (e.g., age,
obesity) have a significant impact on tumor evolution. Thus, we will incorporate these into each of our
focus areas and study tumors in the context of the patient. Our goal is that an improved
understanding of how ITH drives disease progression will lead to changes in clinical practice,
including the development of novel, more effective individualized combination treatment strategies.
Terms: <Active Follow-up><Age><Area><Breast Cancer><Breast Cancer Patient><Breast Neoplasms><Breast Tumor Patient><Breast Tumors><Cancer Cause><Cancer Etiology><Cancers><Cell Body><Cells><Cessation of life><Clinical><Clinical Management><Combined Modality Therapy><Computational toolkit><Death><Development><Disease><Disease Progression><Disorder><ERBB2><ERBB2 gene><Ecologic Systems><Ecological Systems><Ecosystem><Environment><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Evolution><Experimental Models><Failure><Gene Transcription><Genetic><Genetic Transcription><Goals><HER -2><HER-2><HER2><HER2 Genes><HER2/neu><Heterogeneity><Host Factor><Host Factor Protein><Host-Tumor Interaction><Immune><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunotherapy><Integration Host Factors><Intratumoral heterogeneity><Knowledge><Laboratories><Link><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Neoplasms><Metabolic><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Multimodal Therapy><Multimodal Treatment><NEU Oncogene><NEU protein><Neoplasm Metastasis><Obesity><Oncogene ErbB2><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><RNA Expression><Research><Resistance><Secondary Neoplasm><Secondary Tumor><TKR1><Testing><Therapeutic><Transcription><Women's mortality><Work><active followup><adiposity><ages><c-erbB-2><c-erbB-2 Genes><c-erbB-2 Proto-Oncogenes><cancer cell><cancer heterogeneity><cancer metastasis><cancer microenvironment><cancer progression><clinical practice><combination therapy><combined modality treatment><combined treatment><computational toolbox><computational tools><computational toolset><computerized tools><corpulence><customized therapy><customized treatment><death among females><death among women><death in females><death in women><death rate among women><death rate in women><design><designing><developmental><epigenetically><erbB-2 Genes><female death><female mortality><follow up><follow-up><followed up><followup><genomic tools><herstatin><heterogeneity in tumors><host neoplasm interaction><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><insight><interdisciplinary approach><intra-tumoral heterogeneity><intratumor heterogeneity><malignancy><malignant breast tumor><mammary tumor><mortality among females><mortality among women><mortality in females><mortality in women><multi-modal therapy><multi-modal treatment><multidisciplinary approach><neoplasm progression><neoplasm/cancer><neoplastic progression><neu Genes><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><patient oriented outcomes><patient responsibilities><patient specific therapies><patient specific treatment><resistance to therapy><resistant><resistant to therapy><response to therapy><response to treatment><stressor><synergism><synthetic lethal interaction><tailored medical treatment><tailored therapy><tailored treatment><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapeutic response><therapy resistant><therapy response><treatment resistance><treatment response><treatment responsiveness><treatment strategy><tumor><tumor cell metastasis><tumor heterogeneity><tumor microenvironment><tumor progression><unique treatment><women's death><women's death rate>