Identifying Novel Drugable Targets Against TNBC

Institution: University of California, San Francisco
Investigator(s): Andrei Goga, M.D., Ph.D. -
Award Cycle: 2011 (Cycle 17) Grant #: 17IB-0024 Award: $150,000
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2011)

Currently, the greatest clinical challenge in treating breast cancer occurs in those patients whose tumors lack expression of the estrogen and progesterone receptors and the HER2 oncoprotein. No targeted agents currently exist against this aggressive type of receptor 'triple negative' breast cancer that disproportionately affects young African American women and also a substantial number of white American women. We have discovered that triple-negative tumors frequently express high levels of the MYC proto-oncogene. The proposal seeks to identify new “synthetic-lethal” strategies to selectively kill triple-negative breast tumors with MYC overexpression. Synthetic lethality arises when a combination of mutations in two or more genes leads to cell death, whereas a mutation in only one of these genes has little effect. Using this strategy, we can take advantage of the elevated MYC signaling in triple-negative tumors to selectively kill them, while sparing normal tissues in which MYC is expressed at much lower levels. We now seek to identify new molecules, such as cell cycle kinase, which when inhibited can preferentially kill triple-negative breast tumor cells. We hypothesize that additional new targets that may be safer to patients can be identified by using an unbiased shRNA-based screening approach in human cells that have high levels of MYC expression.

Specifically, we plan to conduct an unbiased, high-throughput shRNA screen, focusing on~ 600 kinases and phosphatases, to discover novel MYC-dependent synthetic-lethal interactions in breast cells. In doing so, we will utilize a library of lentiviral shRNA molecules that have been used successfully for similar functional screens. Novel candidates will be further evaluated in human cancer cell lines as well as in mouse models for their impact on triple-negative breast cancer.




Final Report (2013)

Amongst the most aggressive and difficult to treat type of breast cancer is the receptor 'triple negative' breast cancer sub-type that disproportionately affects young African American women but also a substantial number of white American women. Our laboratory seeks to identify more efficacious ways to preferentially kill triple negative breast cancers, which may result in novel therapeutics against this tumor type. Prior work from our lab's research has discovered that triple-negative breast tumors frequently overexpress the MYC oncogene. We have found that patients which overexpress a MYC gene signature have early recurrence and worse prognosis within the ISPY1 clinical trial. We sought to identify new “synthetic-lethal” strategies to selectively kill triple-negative breast tumors with MYC overexpression. Synthetic lethality arises when a combination of mutations in two or more genes leads to cell death, whereas a mutation in only one of these genes has little effect. Using this strategy, we can take advantage of the elevated MYC signaling in triple-negative tumors to selectively kill them, while sparing normal tissues in which MYC is expressed at much lower levels.

We performed a shRNA synthetic-lethal screen to identify new molecules, such as cell cycle kinases, which when inhibited can preferentially kill triple-negative breast tumor cells. The unbiased shRNA-based screening approach was performed in human mammary epithelial cells (HMECs) that have inducible MYC overexpression. A high-throughput screen of ~2000 shRNAs, that target the human kinome (~ 600 kinases) was performed, and identified 13 kinases whose inhibition by >1 shRNAs gave rise to >50% inhibition of cell growth. Two of the kinases identified in our screen, ARK5 and GSK3A, were also recently identified by other studies and shown to have a synthetic-lethal interaction with MYC. These results validated our ability to identify synthetic-lethal targets. We have characterized and validated the most promising of the 11 novel targets identified in this screen, PIM1, using human cancer cell lines as well as human-in-mouse cancer models. Thus both aims of the study have been completed.

Follow-up work is focused on extending these studies using PIM1 inhibitors that are currently in clinical development and extending the human-in-mouse cancer analysis. These studies are distinct from other funded work in our laboratory, and we expect these results will define new synthetic-lethal targets for MYC in aggressive breast cancer




Conference Abstract (2016)

New Approaches to Eradicate Metastatic Breast Cancer

Andrei Goga, MD, PhD / andrei.goga@ucsf.edu
Professor, Dept. Cell & Tissue Biology and Dept. of Medicine
University of California, San Francisco and UCSF Breast Care Center

Despite numerous advances in the advent of chemotherapies and targeted agents over the past decades, metastatic breast cancer remains incurable and essentially a death sentence for afflicted patients. New discoveries including from The Cancer Genome Atlas (TCGA) and our own research groups at UCSF have uncovered new cancer genes and signaling pathways which are altered in breast cancer, raising the hope that selectively blocking these pathways can allow for the precise eradication of breast cancers. Unfortunately, no single targeted drug to date has proven sufficient to durably eradicate metastatic breast cancers, leading to rapid resistance, recurrence of cancer and ultimately death.

The inability of both conventional chemotherapies and targeted agents to eradicate metastatic cancer is due to several key factors. First, breast cancers are very heterogeneous, made up of billions of cells with various genetic alterations. This heterogeneity means that only some, but not all cells within a tumor, will respond to a particular treatment and die. The subset of cells that do not respond continue to grow, replacing the dying cancer cells with resistant tumor cells. Second, cells within a tumor are constantly evolving to become resistant to new insults. Most normal cells within our bodies have exquisitely precise homeostatic mechanisms that prevent their inappropriate proliferation, invasion or growth at distant sites (i.e. metastasis). Unfortunately, these built-in homeostatic mechanisms have been lost in cancer cells, unleashing their ability to grow and disseminate. Rapid tumor evolution is also facilitated by errors within the tumor cell's ability to sense DNA damage and repair it correctly or to segregate chromosomes precisely during cell replication. Thus, the constant generation of mutations within cancer cells contributes to their rapid evolution towards resistance to new targeted therapeutics.

We hypothesize that breast cancer metastasis can be eradicated, tumor recurrence held at bay, and life extended by simultaneously targeting multiple cancer signaling pathways at once. To achieve this, a new general approach for pre-clinical and clinical development is required which relies on measuring tumor response to new agents as the relevant end-point for a therapy. We postulate that selecting the minimal active dose of a therapy on metastatic tumors should allow us to minimize toxicity from these treatments for patients and most importantly allow us to combine multiple agents to simultaneously target cancer cells. Such approaches we predict will maximize tumor killing and limit tumor evolution and recurrence.

We will present data from the Goga Lab at UCSF regarding the identification and targeting of novel pathways for the inhibition of the most challenging and difficult to treat breast cancers. We seek to translate these promising therapies to clinical trials. Our ultimate goal is to combine these novel targeted therapies for the eradication of metastatic breast cancer.



PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression doi:10.1038/nm.4213
Periodical:Nature Medicine
Index Medicus: Nat Med
Authors: Horiuchi, D, Camarda, R, Zhou A, Yau C, Momcilovic, O, Balakrishnan S, et al.
Yr: 2016 Vol: Nbr: Abs: Pg: