Project Details
Description
PROJECT SUMMARY
Treatment with cytotoxic drugs often fail to completely eradicate breast cancers (BrCa) due to viable tumor cells
that persist (“residual tumors”) and represent a reservoir for eventual relapse. In triple-negative breast cancer
(TNBC), a highly lethal BrCa subtype, the presence of post-treatment residual cancer cells is strongly associated
with aggressive disease relapse. Eradicating the drug-persistent TNBC foci could lead to cures, but their
therapeutic vulnerabilities remain elusive, mainly because bona fide preclinical models of this cancer cell state
amenable to genomic and pharmacological interrogation had been lacking. In our recent studies we
demonstrated that treatment-persistent residual tumor cells adopt a distinct and reversible transcriptional
program resembling that of embryonic diapause, a dormant stage of suspended development triggered by stress
and associated with suppressed Myc activity and overall biosynthesis. Importantly, we developed 3-dimensional
(3D) organoid based in vitro models (treatment-persistent organoids, TP-organoids) that faithfully recapitulate
the phenotype and molecular profile of the residual tumors in PDX and in BrCa patients. To our knowledge, this
is a first in vitro model of post-chemotherapy residual dormant cancer lesions. Our molecular and functional
analyses strongly suggest that chemo-persistent dormant tumor cells possess distinct genomic and
pharmacological vulnerabilities that are not reflected by historical cancer models (e.g. 2D cultures or
conventional 3D/organoid cultures). The novelty and relevance of our models warrant the evaluation of putative
mediators of the drug-persistent cancer cell state, which could reveal new, previously unappreciated, therapeutic
targets for this clinically critical setting. In this exploratory project, we will combine our TNBC TP-organoid models
of drug-persistent dormancy with genomic and pharmacological methods to i) identify the key mediators
controlling TNBC cell exit from the dormancy state; and ii) develop therapeutic approaches that specifically kill
dormant drug-persistent TNBC tumors. We will apply controllable loss-of-function (LOF) and gain-of-function
(GOF) techniques to determine whether reactivation of Myc and/or other genes is necessary or sufficient for
BrCa cells to exit dormancy. Similarly, we will use LOF approaches targeting genes commonly upregulated in
our preclinical models of residual disease to assess their role on the viability of diapause-like persistent TNBC
cells. In parallel, we will leverage the high-throughput capacity of our TP-organoid systems to map the landscape
of pharmacological vulnerabilities of the chemo-persistent TNBC cells. The therapeutic value of candidate targets
that enable the viability of persistent TNBC cells, or their exit from the dormant state, will be validated in
appropriate in vivo residual disease models. This exploratory project will outline a first preclinical framework of
therapeutic approaches to specifically target diapause-like drug-persistent TNBC tumors. Specifically targeting
the candidate mediators that enable the viability during, or the exit from, treatment-induced protective dormancy
of persistent residual cancer cells could lead to durable responses or even tumor eradication.
Status | Finished |
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Effective start/end date | 5/2/22 → 4/30/23 |
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