A Vision to End HER2-Driven Cancer Death (Mark Moasser)
Although much progress has been made in the treatment of early stage breast cancer, advanced stage breast cancer remains uniformly fatal. The subtype of breast cancer closest to this milestone is the HER2 positive subtype. Our depth of scientific insight about this subtype is closest to the critical threshold that could potentially lead to eradicative therapies. But more work is required. Our overall program seeks to study in molecular depth how the HER2 signal is generated by overexpression. To do this, we are trying to overcome the principal barriers that have been to purify and determine the crystal structures of the HER2 kinase, its partner HER3, and how they partner with each other. This will eventually lead to treatments that effectively inactivate HER2, something that has remained elusive to date.
Mapping the Impact of Tumor Mutations on Patient Drug Responses in Triple Negative Breast Cancer (Sourav Bandyopadhyay)
Cancer is driven by mutations in oncogenes and tumor suppressors. In breast cancer, activating mutations in an oncogene such as PIK3CA, EGFR, HER2 or inactivation of tumor suppressors P53 or Rb are evident in nearly every tumor. For a some genes such as HER2 and EGFR, mutation in these oncogenes are used as markers for personalized drug treatments targeting these mutant oncogenes which tumors depend on for growth and survival.
Beyond a few key examples the influence of aberrant oncogene activation on patient drug responses is almost completely unknown. To address this issue we are developing technologies to measure the influence of a panel oncogenic kinases in breast cancer on the susceptibility to ~100 anti-cancer drugs. The aim of these studies is to derive a chemical-genetic interaction map that can guide the selection of personalized therapeutic regimens based on selected patient biomarkers. Our efforts are supported by valuable collaborations at UCSF in the interrogation of mechanistic insights from our screens (Frank McCormick), identification of clinically relevant markers (Andrei Goga), and query of patient signatures in ongoing clinical trials (Laura Van’t Veer).
Combinatorial Therapies to Eradicate Metastatic Breast Cancer (Andrei Goga)
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. 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.
Functional detection of the targetable kinome of chemotherapy-resistant triple-negative breast cancer (Jean-Phillipe Coppé)
Triple-negative breast cancer (TNBC) accounts for approximately 15%-25% of all breast cancer cases. The etiology of TNBCs and their therapeutic response remain elusive. Early complete response does not necessarily correlate with overall survival, and relapse patterns differ from hormone-positive breast cancers. It has been particularly complicated to define optimal chemotherapy regimens adapted to TNBC patients. The management of TNBC cases will significantly improve once mechanisms responsible for TNBC resistance to chemotherapies will be identified. Evidences suggest that chemotherapy-resistant TNBC cells display deregulated kinase-dependent signaling cascades1-2. We hypothesize that chemotherapy-resistant TNBC cells harbor uniquely adapted phospho-signaling networks, and that some specific kinases at the heart of these divergent phospho-circuits can be targeted with inhibitors to successfully restore therapeutic response.
To test this hypothesis, TNBC cell lines will be treated with Doxorubicin, Carboplatin, or Paclitaxel using regimens closely mimicking those used in the clinic to create resistant cell lines. The active, oncogenic phospho-signatures of TNBC cells and their chemotherapy-resistant counterparts will then be analyzed using a new high throughput experimental platform that monitors the level of activity of myriad kinases at once. This technique uses phospho-sensing probes in an aqueous-based assay to simultaneously and directly measure the phospho-catalytic activity of phosphorylating enzymes. Kinase activity signatures will be compared to map deranged signaling networks. We postulate that these kinase profiles will reflect unique kinase dependence or addiction mechanisms causing (or indispensable to) chemotherapy resistant phenotypes. The few, most hyperactive, conserved kinases that will emerge as best candidates, will be tested in resistant TNBC cells using approved or investigational drug inhibitors and assayed for increased sensitivity to cell death, or reduced cell growth. The successful completion of our objectives will identify how chemotherapeutic interventions lead to the re-programming of phospho-circuits, and which kinases are the targetable weaknesses of resistant triple-negative breast cancer cells.
Drug Penetrance as a Predictor of Response to Veliparib/Carboplatin in triple negative breast cancer (Rada Savic, Imke Bartelink)
Background and hypotheses: TNBC is an aggressive subtype of breast cancer with inadequate therapeutic options, disproportionately affecting young Afro-American and African women. PARP inhibitors are promising in this type of cancer, but in I-SPY 2 approximately 42% of TNBC did not optimally respond to the veliparib based treatment for currently unknown reasons. There is little data available on whether veliparib reaches all tumor cells in individual patients thus, all patients receive the same drug dose. Previous research of other targeted therapies shows that standardized dosing leads to some variability drug concentrations in blood between patients, and a much higher variability in drug concentrations within solid tumors. If drug concentrations in the tumor cells are limited, this may lead to decreased response or resistance to the drug. Therefore we hypothesize (1) low or variable penetration of veliparib and carboplatin between and within the tumors explains why some TNBC patients failed to respond to PARPi in I-SPY2. Recently, we received the BOP 2014 Therapeutics and Clinical Trials Poster Award, when we demonstrated that Matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI) is an effective and precise method to measure the penetration of veliparib and carboplatin concentrations in mouse-tumors. Characteristics of the tumor (e.g. how many blood vessels reach the tumor or what is the cell density of the tumor) may explain the differences in drug penetration and efficacy. Therefore we aim to measure vessel density, cell viability, cell density and determine which of these variables are predictive of drug penetration and activity. In addition we hypothesize (2) that information from contrast-enhanced MRI scans can be used to understand the variability in penetration of veliparib and carboplatin.
Impact and applicability: Genomics, the study of all genes in a cell or tissue and how they express, has enabled personalized medicine and targeting therapies in breast cancer; however there is no precision in the dosing of these targeted therapies such as veliparib. We want to identify which patients are likely to respond to the novel drugs before or very early in treatment. By focusing on the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888, we want to help optimize treatment of patients with triple-negative breast cancer (TNBC) especially. Ultimately we want to individualize the drug doses for patients who have low tumor penetrance. By improving dosing regimens (e.g. more frequent administrations) in patients with potentially low tumor uptake, these patients have a greater chance of responding to therapy. We anticipate being ready to propose the first individualized drug treatments in 2016.
Predictive Biomarkers and Novel Targets in BC at the Immune-Oncogenic Interface (Denise Wolf, Max Krummel, Michael Campbell)
Breast cancer is not a single disease and treatments will be required to identify which patients are likely to respond to which therapies. We are beginning to make terrific advances in designing ³immunotherapies² based on harnessing the body¹s own response, typically one or more components of the immune response, to aid in eradicating or controlling cancer. However, the first round of these therapies are either working remarkably well or not working at all, depending on the patient. This makes it clear that we need to understand first how the immune system is arrayed in each type of breast cancer in order to choose and design the most efficient drug.
The proposal will start to break the immune response into subclasses that match or Œdefine¹ the disease. The proposal will first tease apart which populations of immune cells are already present in the tumor. This is analogous to figuring out what army is present on the battlefield. Then, the proposal will determine which molecules are being expressed in the key subsets of cells. The molecular contents of a cell tells you what that cell can and cannot do to assist in clearing a tumor. Since in many cases we need to activate some cells while others, this latter point is quite important. At the end of this modest proposal, we will have accrued preliminary data that defines BC by its immune infiltrate and thus proposes new ways to diagnose AND treat individual patients.
Development of Targeted Therapeutics for Triple Negative Breast Cancer (Luika Timmerman)
Triple-Negative Breast Cancer (TNBC) is the most deadly form of breast cancer, comprising 15- 20% of all cases. Patients with TNBC are generally younger, disproportionally of African-American and Hispanic heritage, with more rapid disease progression and the poorest clinical outcomes. TNBC tumors are so named because they do not express the estrogen receptor, progesterone receptor, or the HER2 receptor tyrosine kinase. Tumors that express the estrogen receptor or the HER2 receptor can be treated with therapeutics that specifically target these receptors. This produces potent anti-tumor activity that spares most normal, receptor-negative tissues. In contrast, there are no therapeutics that specifically target receptors on TNBC. Therefore TNBC patients must be treated with combinations of standard chemotherapeutics and radiation, which affect all cells of the body and have doses limited by toxic effects on normal tissues.
In a computer-based analysis of gene expression data, we identified a new, large class of proteins that are overexpressed by TNBC. Tumors use these proteins to acquire nutrients from a patient’s circulatory system to support growth and metastatic spread. Our early studies indicate that blocking some of these proteins can kill tumors, or halt or slow their growth. We are translating these experimental results into novel, potent drugs for use in TNBC patients. Our first success story involves the identification of a transporter for the amino acid cystine, which is present on the surface of about 1/2 of all TNBC. This transporter, named xCT, is expressed by few normal cells in the body. In animal experiments, normal cells that do express xCT do not appear to be harmed if it is blocked or if the DNA encoding it is entirely removed from the genome. This makes xCT an ideal, tumor-specific drug target. A major focus of our ongoing work is to leverage these findings into an urgently needed xCT-specific therapeutic for TNBC. In pilot studies, we also found that xCT inhibition can make tumor cells more sensitive to conventional chemotherapeutics such as carboplatin. This is particularly exciting, since the ability to specifically sensitize tumors to these mainstay chemotherapeutics should allow physicians to give patients lower chemotherapeutic doses, thereby reducing the deleterious effects on normal tissues while increasing the tumor killing. We are currently cataloging the variety of chemotherapeutics and schedules of radiation therapy that can be made more potent by xCT inhibition.