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--- | ||
layout: secondary | ||
title: Data | ||
section_id: data | ||
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data: | ||
publication: | ||
title: AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution | ||
journal: 'TBA' | ||
authors: 'Schade A, Perurena N, Yang Y, Rodriguez CL, Krishnan A, Loi P, Mastellone GM, Pilla NF, Watanabe M, Xu Y, Nguyen V, Ota K, Davis RA, Mattioli K, Xiang D, Zoeller JL, Morganti S, Garrido-Castro AC, Tolaney S, Li Z, Barbie DA, Sorger PK, Helin K, Santagata S, Knott SRV, Cichowski K.' | ||
description: 'Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy, however responses are typically short-lived. Thus, there is an urgent need to develop more effective treatments. PI3K pathway components represent plausible therapeutic targets, as at least 70% of TNBCs have PIK3CA/AKT1/PTEN alterations. However, unlike hormone receptor-positive tumors, it is still unclear if or how PI3K pathway inhibitors will be effective in triple-negative disease. Here we describe a promising AKT inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors potently synergize with agents that suppress the histone methyltransferase, EZH2, and promote robust tumor regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once differentiated, these agents kill TNBCs by hijacking signals that normally drive mammary gland involution. Importantly, using a machine learning approach we developed a classifier that can be used to predict sensitivity. Together these findings identify a promising therapeutic strategy for this highly aggressive tumor type and illustrate how deregulated epigenetic enzymes can insulate tumors from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit.' | ||
links: | ||
- Data Access: https://github.com/labsyspharm/cichowski-santagata-sorger-2024/ | ||
--- | ||
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{% assign urlParts = page.url | split: '/' %} | ||
{% assign sectionId = urlParts[-1] %} | ||
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{% include atlas-dataset-info.html | ||
sectionId=sectionId | ||
pubData=page.data | ||
thumbnailDir=sectionId %} | ||
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## Contents | ||
* [Graphical Abstract](#graphical-abstract) | ||
* [Data Access](#data-access) | ||
* [Funding](#funding) | ||
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### Graphical Abstract | ||
{% include enlarge-image.html src='publications/cichowski-santagata-sorger-2024.PNG' alt='EZH2 + AKT inhibitors in TNBC' %} | ||
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### Data Explorations | ||
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{% | ||
assign stories = site.data-cards | ||
| where_exp: "item", "item.url contains 'cichowski-santagata-sorger-2024'" | ||
| where_exp: "item", "item.hide != true" | ||
%} | ||
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{% assign dataCardArray = '' | split: '' %} | ||
{% for s in stories %} | ||
{% unless s.url contains '-overview' %} | ||
{% assign dataCardArray = dataCardArray | push: s %} | ||
{% endunless %} | ||
{% endfor %} | ||
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{% if dataCardArray.size > 0 %} | ||
{% include cards.html cards=dataCardArray %} | ||
{% endif %} | ||
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## Data Access | ||
Instructions to access data will be posted to the [GitHub repository](https://github.com/labsyspharm/cichowski-santagata-sorger-2024/) associated with this publication. | ||
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### Funding | ||
This work was supported by a grant from the Cancer Research UK Grand Challenge and the Mark Foundation for Cancer Research to the SPECIFICANCER team (KC) and a DOD BC201085P1 Transformative Breast Cancer Consortium Award (KC). A.S. was supported by an American Cancer Society Postdoctoral Fellowship (PF-22-040-01-ET). N.P. was supported by AACR-AstraZeneca Breast Cancer Research Fellowship (20-40-12-PERU). K.M. was supported by NHGRI F32 #1F32HG012318-01. S.S. was funded by National Cancer Institute grant U54-CA225088 and the BWH President’s Scholar Award. Z.L. was supported by NIH grant R01 CA222560. |
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--- | ||
title: "HCI-004 PDX tumor: EZH2i/AKTi Combo Treatment Day 1" | ||
image: https://s3.amazonaws.com/www.cycif.org/cichowski-santagata-sorger-2024/Combo-day-1/panCK_0000ff-Ki67_ff6f00-cPARP_ffffff-CK14_00ff00-CK8_ff0000.jpg | ||
date: '2024-03-21' | ||
minerva_link: https://s3.amazonaws.com/www.cycif.org/cichowski-santagata-sorger-2024/Combo-day-1/index.html | ||
show_page_link: false | ||
info_link: https://s3.amazonaws.com/www.cycif.org/cichowski-santagata-sorger-2024 | ||
featured: false | ||
--- |
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--- | ||
title: "HCI-004: PDX tumor EZH2i/AKTi Combo Treatment Day 2" | ||
image: https://s3.amazonaws.com/www.cycif.org/cichowski-santagata-sorger-2024/Combo-day-2/panCK_0000ff-Ki67_ff6f00-cPARP_ffffff-CK14_00ff00-CK8_ff0000.jpg | ||
date: '2024-03-21' | ||
minerva_link: https://s3.amazonaws.com/www.cycif.org/cichowski-santagata-sorger-2024/Combo-day-2/index.html | ||
show_page_link: false | ||
info_link: https://s3.amazonaws.com/www.cycif.org/cichowski-santagata-sorger-2024 | ||
featured: false | ||
--- |
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--- | ||
title: "HCI-004 PDX tumor: EZH2i/AKTi Combo Treatment Day 30" | ||
image: https://s3.amazonaws.com/www.cycif.org/cichowski-santagata-sorger-2024/Combo-day-30/panCK_0000ff-Ki67_ff6f00-cPARP_ffffff-CK14_00ff00-CK8_ff0000.jpg | ||
date: '2024-03-21' | ||
minerva_link: https://s3.amazonaws.com/www.cycif.org/cichowski-santagata-sorger-2024/Combo-day-30/index.html | ||
show_page_link: false | ||
info_link: https://s3.amazonaws.com/www.cycif.org/cichowski-santagata-sorger-2024 | ||
featured: false | ||
--- |
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--- | ||
title: "HCI-004 PDX tumor: Vehicle Treatment" | ||
image: https://s3.amazonaws.com/www.cycif.org/cichowski-santagata-sorger-2024/Vehicle/panCK_0000ff-Ki67_ff6f00-cPARP_ffffff-CK14_00ff00-CK8_ff0000.jpg | ||
date: '2024-03-21' | ||
minerva_link: https://s3.amazonaws.com/www.cycif.org/cichowski-santagata-sorger-2024/Vehicle/index.html | ||
show_page_link: false | ||
info_link: https://s3.amazonaws.com/www.cycif.org/cichowski-santagata-sorger-2024 | ||
featured: false | ||
--- |
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...ons/AKT-and-EZH2-inhibitors-kill-TNBCs-by-hijacking-mechanisms-of-involution.md
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--- | ||
title: 'AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution' | ||
contributors: 'Schade A, Perurena N, Yang Y, Rodriguez CL, Krishnan A, Loi P, Mastellone GM, Pilla NF, Watanabe M, Xu Y, Nguyen V, Ota K, Davis RA, Mattioli K, Xiang D, Zoeller JL, Morganti S, Garrido-Castro AC, Tolaney S, Li Z, Barbie DA, Sorger PK, Helin K, Santagata S, Knott SRV, Cichowski K. (2024).' | ||
publication: TBA | ||
publication_link: | ||
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image: publications/cichowski-santagata-sorger-2024.PNG | ||
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group: featured | ||
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date: 2024-02-29 | ||
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minerva_link: | ||
pubmed_link: | ||
dataset_link: /atlas-datasets/cichowski-santagata-sorger-2024/ | ||
preprint_link: | ||
pdf_link: | ||
show_page_link: false | ||
--- |
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--- | ||
# name of the software | ||
title: Orion | ||
# summary of the tool | ||
description: | | ||
Orion is a method for collecting one-shot 18-plex immunofluorescence images and diagnostic-grade H&E images from the same samples. The Orion method was developed in collaboration with RareCyte Inc. and uses a specialized microscope and fluorescent antibodies (known as ArgoFluors™), which can be imaged simultaneously and spectrally unmixed. We show that same-slide H&E and IF images provide complementary information that can be used to train ML models that effectively predict cancer progression. | ||
# thumbnail image, can be a logo too | ||
image: software/orion.png | ||
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# link to the publication | ||
publication: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc10368530/ | ||
# link to associated data | ||
dataset_link: https://www.tissue-atlas.org/atlas-datasets/lin-chen-campton-2023/ | ||
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# for sorting purpose | ||
date: 2020-01-02 | ||
# set the type for this item - will determine which page it appears on: | ||
# [ software | method ] | ||
type: method | ||
--- |
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