TBBCF Research Grant Recipients
Click here for a listing of publications with acknowledgements of support from the Terri Brodeur Breast Cancer Foundation. Click here for a listing of grant recipient abstracts – 2007-2018.
| Grant Year | Grant Recipient | Research Institute |
|---|---|---|
| 2019 | Garrido-Castro, Ana, MD | Dana-Farber Cancer Institute |
| Daniels, Veerle, PhD | Dana-Farber Cancer Institute | |
| Hu, Jing, PhD | Memorial Sloan Kettering Cancer Center | |
| Spring, Laura, MD | Massachusetts General Hospital | |
| 2018 | Dasgupta, Arko, PhD | Fred Hutchinson Cancer Research Center |
| Sun, Sheng, PhD | Mass General Hospital Cancer Center | |
| Waks, Adrienne Gropper, MD | Dana-Farber Cancer Institute | |
| 2017 | Li, Ji, PhD | Dana-Farber Cancer Institute |
| Meyer, Aaron, PhD | Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology | |
| Parsons, Heather, PhD | Dana-Farber Cancer Institute | |
| 2016 | Albrengues, Jean, PhD | Cold Spring Harbor Laboratory |
| Karayvaz, Mihriban, PhD | Mass General Hospital Cancer Center | |
| Stover, Daniel, MD | Dana-Farber Cancer Institute | |
| Toska, Eneda, PhD | Memorial Sloan Kettering | |
| 2015 | Dhimolea, Eugen, PhD | Dana-Farber Cancer Institute |
| Ilic, Nina, PhD | Dana-Farber Cancer Institute | |
| Pavlova, Natalya, PhD | Memorial Sloan Kettering | |
| 2014 | Carmona, Javier PhD | Memorial Sloan Kettering |
| Hofstatter, Erin MD | Smilow Cancer Hospital at Yale New Haven | |
| Page, David MD | Memorial Sloan Kettering | |
| 2013 | Vora, Sadhna R. MD | Dana-Farber Cancer Institute |
| Anczukow-Camarda, Olga, PhD | Cold Spring Harbor Laboratory | |
| Rossetti, Stephano PhD | Roswell Park Alliance Foundation | |
| 2012 | Diab, Adi MD | Memorial Sloan Kettering |
| Jhaveri, Komal, MD | NYU School of Medicine | |
| Brastianos, Priscilla MD | Dana-Farber Cancer Institute | |
| 2011 | Gucalp, Ayca MD | Memorial Sloan Kettering |
| Walczak, Maciej MD | Memorial Sloan Kettering | |
| Li, Yang PhD | Dana-Farber Cancer Institute | |
| 2010 | Gajria, Devika MD | Memorial Sloan Kettering |
| Kass, Elizabeth MD | Memorial Sloan Kettering | |
| Zhou, Penghui MD | Dana-Farber Cancer Institute | |
| Kochupurakki, Bose PhD | Dana-Farber Cancer Institute | |
| 2009 | Bialucha, Carl Uli PhD | Cold Spring Harbor Laboratory |
| Kutuk, Ozgur MD, PhD | Dana-Farber Cancer Institute | |
| Bailey, Shannon T. MD | Dana-Farber Cancer Institute | |
| Zang, Qing PhD | Dana-Farber Cancer Institute | |
| 2008 | Irie, Hanna Y MD, PhD | Mount Sinai School of Medicine |
| Choudhury, Sibgat PhD | Dana-Farber Cancer Institute | |
| Fertuck, Kirsten PhD | Dana-Farber Cancer Institute | |
| 2007 | Oliver, Andrea MD | Dana-Farber Cancer Institute |
| Chatterjee, Samit PhD | Cold Spring Harbor Laboratory | |
| Mayer, Erica MD, MPH | Dana-Farber Cancer Institute | |
| Lee, Dongoo PhD | Memorial Sloan Kettering |
Oliver, Andrea MD
Dr. Oliver studied molecular pathways conferring Tamoxifin and Herceptin resistance to metastatic cells.
Chatterjee, Samit PhD
Dr. Chatterjee, a Molecular Cell Biologist, studied the molecular determinants of cellular polarity. It is thought that dysregulation in cell polarity may be a preamble to formation of early epithelial breast malignancies. This proposal was executed at Cold Spring Harbor
Mayer, Erica MD, MPH
Dr. Mayer studied the vascular injury and hypertensive liabilities of Avastin which limit its therapeutic potential. Understanding this problem could improve treatment regimes and ultimately outcomes as well.
Lee, Dongjoo PhD
Dr. Dongjoo Lee, a Clinical Research Oncologist at the Memorial Sloan-Kettering Institute, developed a chemical synthesis of the potent novel carbohydrate-based glycopeptides anticancer vaccine candidate that will be evaluated for immunogenecity against a variety of human cancer.
Choudhury, Sibgat PhD.
Dr. Choudhury looked at putative mammary precurser cells that are resistent in breast tissue. Such cells were hoped to provide clues as to the progression of breast cancer.
Fertuck, Kirsten PhD
Dr. Fertuck is a cell biologist studying estrogen receptor signaling in a premier laboratory guided by Myles Brown. Estrogen has a well documented but only partially understood role in etiology of breast cancer even though the activity of several successful drugs are modeled on this important horŵoŶe. Dr. FertuĐk͛s projeĐt ǁas desigŶed to proǀide a ŵore preĐise piĐture of hoǁ estrogeŶ interacts with the breast cancer genome therby to improved chemotherapies and treatment regimes.
Irie, Hanna Y MD, PhD.
Dr. Irie, a cell biologist, investigated the bais of the resistance of cancer cells to undergo programmed cell death. She sought to understand why certain genes render cancer cells immortal and difficult to eradicate.
Bialucha, Carl Uli PhD
Dr. Bialucha has developed a sophisticated technology that can correctly identify the specific gene deletions that drive breast cancer. Results from these studies could lead to a new generation of therapies and diagnostic tools.
Kutuk, Ozgur MD, PhD
Resistance to chemotherapy is a major problem in the fight against breast cancer. Dr. Kutuk’s research involved exploring the pathways of cell death activated by chemotherapeutics in breast cancer cells and the regulation of these pathways by Bcl-2 proteins.
Bailey, Shannon T. MD
Dr. Bailey’s research focuses on how the estrogen receptor influences the cell death process.
Zang, Qing PhD
Normal cells have a remarkable ability to sense oxygen and nutrients in their environment and to respond. Cancer cells possess the same machinery but respond in an unhealthy metastatic manner. Dr Zhang studied one such oxygen sensing system in breast cancer cells that is believed to provoke tumors to grow in an uncontrolled fashion.
Zhou, Penghui MD
It has always been a mystery as to why a person’s own immune system doesn’t fight off tumors as it does infections. In fact, the immune system’s major weapon, the T-cell, does attack tumors, but it quickly gets deactivated in the tumor environment. Dr. Zhou dedicated his research to understanding why this occurs with the hopes of learning enough about this process to overcome it.
Kochupurakki, Bose PhD
Specific aims of Dr. Kochupurakki’s proposed work were to determine the sub-type specificity of activated NF-kB in tumor samples; analyze the phenotype of mammary epithelial cells expressing constitutively active mutant of NF-kB and screen for drugs that will inhibit cell transformation; and determine the activation status of NF-kB in a large set of breast cancer cell lines and derive a gene expression signature for constitutively active NF-kB.
Kass, Elizabeth MD
It would be of great value to understand how breast cancer develops. The research of Dr. Kass probed breast cancer tumorigenesis. Events that occur during the earliest stages of mammary development are believed to alter the lifetime risk of breast cancer. Her research seeks to elucidate how specific developmental changes in mammary epithelium affect the molecular mechanisms by which cells respond to DNA damage and potentially prevent tumor formation.
Li, Yang, PhD
A major problem that plagues breast cancer therapy is the resistance that some patients have to drugs that can treat this disease. Dr. li has discovered that patients with high levels of Lysosomalassociated protein transmembrane-4beta (LAPTM4B) are the very patients for whom chemotherapy is unsuccessful. This work alone is valuable in itself because it could be used to predict which patients will benefit from drug treatments and those who won’t. Dr Li advanced this by studying what mechanistic role LAPTM4B is playing in the process. He believes that LAPTM4B enables tumor cells to eliminate naturally existing cell death triggers, thereby allowing the tumor to continue to grow.
Gucalp, Ayca MD
One of the great frustrations in treating breast cancer results from some patients being resistant to therapies that work successfully in others. Dr. Gucalp. Dr. Devika Gajria (MSKCC) believes that such resistance can be overcome by combining two novel clinical drugs whose activities could synergize and provide enough potency to overcome such resistance. Dr. Gajria will first find the most appropriate dosing regimen to administer this combination and then study it in breast cancer patients whose disease cannot be cured with other drugs.
Walczak, Maciej MD
A major challenge in fighting breast cancer is trying to block cancer cell metastasis – the process where cancer cells travel and proliferate into other organs. Japanese scientists have previously isolated a compound called “migrastatin” which is able to inhibit metastasis in vitro. Unfortunately, migrastatin has only modest efficacy and does not have the necessary properties to be a drug. Dr. Walczak synthesized and evaluated novel derivatives of migrastatin which should fix the problems of the parent compound and yield novel agents to prevent breast cancer metastasis.
Brastianos, Pricilla MD
Dr. Brastianos studied the unique gene mutations that lead to brain metastases which occur in breast cancer patients. Brain metastases occur in up to 30% of patients with metastatic breast cancer. Survival continues to be dismal and ranges from 3 months to 23 months after the diagnosis of a metastasis in the central nervous system. Using a rapid and robust technique called whole-exome sequencing; Dr. Brastianos looked to identify the genes that direct metastases to the brain thereby opening new avenues to both predict and to treat this currently terminal condition.
Diab, Adi MD
Dr. Diab evaluated the safety of two strategies called “cryoablation” and “immune therapy” in early stage breast cancer patients. “Cryoablation” is a procedure in which very cold temperatures are applied to kill the cancer cells. The killed cancer cells can be recognized by a person’s immune system. The “immune therapy” in Dr Diab’s study is an FDA approved antibody drug called ipilimumab. It is believed that this combination could provide a new approach for treating breast cancer.
Jhaveri, Komal, MD
Dr. Jhaveri is evaluating the effect of a potent class of drugs called HSP90 inhibitors in combination with the established standard-or-care therapy, Paclitaxel and Herceptin in patients with metastatic disease. HSP90 is a protein found in some cancers, and helps the cancer cell to divide and change at the alarming rates observed. In addition, Dr. Jhaveri is employing a “personalized” approach to patient selection by using an imaging agent developed at Memorial Sloan Kettering that tells the oncologist if HSP90 is present in the tumor. It is believed that this approach will lead to better care and outcomes for this patient group.
Anczukow-Camarda, Olga, PhD
Cancer is a very complex disease in which many cellular processes are deregulated. Understanding cellular processes and molecular interactions is necessary to understand how cancer starts and can be treated. Dr. Anczukow-Camarda works on “splicing,” a critical step in gene expression that determines how genetic instructions in DNA are cut and pasted together as RNA intermediates to form the templates for producing proteins. By identifying splicing factors, this research will lead to new breast cancer therapies.
Vora, Sadhna R. MD
Roughly 30% of breast cancers demonstrate a mutation in the gene PIK3CA, which drives their growth by activation of the PI3K pathway. While these breast cancers may initially respond to drugs that target this pathway, they ultimately grow again by developing ways to overcome the action of the drug. Dr. Vora’s work examines how tumors become resistant to these drugs and seeks ways to overcome resistance with combinations of drugs that target specific pathways that drive cancer.
Gajria, Devika MD
One of the great frustrations in treating breast cancer results from some patients being resistant to therapies that work successfully in others. Dr. Gajria believes that such resistance can be overcome by combining two novel clinical drugs whose activities could synergize and provide enough potency to overcome such resistance. Dr. Gajria is searching the most appropriate dosing regimen to administer this combination and then study it in breast cancer patients whose disease cannot be cured with other drugs.
Rossetti, Stephano PhD
Breast cancer cells typically produce more ribosomes, the cellular machines that synthesize proteins, to meet their increased metabolic demand. While increased ribosome production has been used for many years as a diagnostic and prognostic marker of breast cancer, it is currently unknown whether this feature is a cause or a consequence of breast cancer. This project aims to answer this long standing question. We plan to test whether increased ribosome production is a breast cancer “driver” capable of inducing early breast cancer stages.
Carmona, Javier PhD
The efficacy of targeted therapies in cancer patients is often limited by the emergence of resistance. Anti-HER2 agents, specifically trastuzumab, have significantly improved survival rates in HER2 positive breast cancer patients. However, a considerable number of patients exhibit primary resistance or become refractory after initial responses. Therefore, understanding the mechanisms by which cancer cells escape treatment is mandatory to design better therapeutic strategies. To do so, we will perform targeted exome sequencing on a clinical cohort of patients treated with HER2 agents that will uncover the genetic alterations triggering therapy refractoriness, and the mutations driving response to therapy. The validation of these findings will provide biomarkers useful for stratification of treatment regimens and identify potential new therapeutic targets.
Page, David PhD
The immune system is highly capable of recognizing and killing cancer, but is in constant struggle with cancer’s evolving ability to “escape” the immune response. A new drug called tremelimumab serves to restore the anti-cancer immune response by releasing a natural “brake” found on a subset of immune cells. Dr. Page is conducting a clinical trial evaluating whether tremelimumab could be combined with therapeutic brain radiation to facilitate durable disease control in patients with newly diagnosed breast cancer brain metastases.
Hofstatter, Erin MD
Age appears to be the single most important risk factor for the development of breast cancer; however, why increasing age is associated with increasing incidence of breast cancer remains incompletely understood. In our study, we will examine epigenetic changes in breast tissue and blood samples from women with breast cancer at young (<45) and older ages (>65), and compare them to samples from age-matched healthy women. We hypothesize that women who accumulate more epigenetic changes at a younger age are at higher risk to develop breast cancer, and aim to identify an epigenetic pattern that could demonstrate premature “aging” of breast tissue.
Dhimolea, Eugen PhD
Most breast cancer patients are Estrogen Receptor (ER)-positive and are treated with antiestrogens after the surgical removal of the mammary tumor. Nonetheless approximately 1/3 of the patients develop metastases, frequently in the bone, that do not respond to treatment. The preference of breast cancer for dissemination to specific tissues (organotropism) indicates a favorable local microenvironment in these organs. While the antiestrogen resistance of ER+ metastatic tumors has been mainly attributed to acquisition of mutations, the role of the metastatic microenvironment in the emergence of these mutations has not been clarified. We will implant patient-derived breast cancer samples in an animal model of “humanized” bone tissue to determine how the bone marrow niche affects the selection of mutations that lead to antiestrogen resistance. This study is also expected to identify plausible therapeutic targets and potentially to generate a novel tool of personalizedmedicine for the evaluation of treatment options in patients with advanced breast cancer.
Ilic, Nina PhD
Activating mutations in the PIK3CA gene are found in approximately 30% of breast cancers and promote growth of these tumors. Despite extensive efforts, direct pharmacologic inhibition of this mutant lesion has shown limited patient benefit in recent clinical trials. Therefore, to provide novel personalized treatment options for breast cancer patients, it is critical that we identify alternative gene vulnerabilities that can be targeted for therapy. To discover such mutant PIK3CA-specific vulnerabilities, we interrogated genome-wide genetic dependency data from multiple human cancer cell lines. Here we identified and subsequently validated three integral Krebs cycle genes, as specific gene-dependencies in this group of tumors. As a Terri Brodeur research fellow, Dr. Ilic will explore these newly identified metabolic vulnerabilities in PIK3CA mutant breast cancers to evaluate their potential for precise therapeutic strategy.
Pavlova, Natalya PhD
Dr. Paǀloǀa͛s ϮϬϭϱ Terri Brodeur Breast CaŶĐer FouŶdatioŶ felloǁship aǁard foĐuses oŶ the investigation of metabolic adaptations which drive breast cancer metastasis. Cancer-specific metabolic alterations and their functional contribution to tumorigenesis have been under intense investigation in the recent years. However, we still lack a clear picture of how these alterations align with the multistep nature of tumorigenesis. In particular, relatively little is known about metabolic adaptations which distinguish metastatic cancer cells from their non-metastatic counterparts. As preliminary data indicate, metastatic isolates from triple negative breast cancer cells display distinct alterations in the biosynthesis and catabolism of amino acids. In the proposed study, Dr. Pavlova intends to investigate the functional contribution of these metabolic adaptations to metastatic colonization and growth, and determine whether such adaptations promote the resistance of metastatic cells to nutrient deprivation and oxidative stress. Furthermore, using pre-clinical models of breast cancer metastasis, Dr. Pavlova will explore whether such metabolic adaptations can be exploited as targets for anti-metastasis therapy.
Albrengues, Jean PhD
Dr. Albrengues’ 2016 Terri Brodeur Breast Cancer Foundation fellowship award focuses on the regulation of breast cancer dormancy by the tumor microenvironment. Metastatic breast cancer relapse occurring years after a seemingly successful treatment is preceded by an interlude, termed dormancy, when the cancer remains non-proliferative and undetected at a secondary site. Unfortunately, these dormant tumor cells appear to be refractory to available therapies and the cues mediating their reawakening are largely unknown. Dr. Albrengues’ hypothesized that dormant cells are awakened by signals from inflammatory immune cells, which also provide cues for aggressive behavior of cancer cells in the primary tumor. To test this hypothesis, he will use newly developed in vitro and in vivo models of dormancy and reawakening. To visualize the interactions with the surroundings, the survival, and the proliferation of tumor cells in situ, he will use microscopy in lungs of living mice and determine how these parameters changes when the disseminated, dormant tumor cells are induced to reawaken. Using pharmacological and genetic approaches, he will identify and target specific signals between inflammatory and cancer cells during experimental manipulation of dormancy. Together, these approaches will allow him to determine how communications between tumor cells and inflammatory microenvironment contribute to the reawakening and therapy resistance of the dormant cells. This analysis will likely reveal new strategies for treatment of dormant disease.
Karaayvaz, Mihriban PhD
Making a major impact on the incidence and lethality of breast cancer will require a detailed understanding of the early events in breast cancer development, particularly in women who are at the highest risk of developing these cancers such as those who carry mutations in the BRCA1/2 genes. Unfortunately, few breast cancer studies are focused on these early events and on breast cancer prevention. We have established a method to analyze distinct cell populations from healthy mastectomy tissues of BRCA1/2 carriers and from tissues of patients undergoing reduction mammoplasty (non-carrier controls). Through detailed molecular analysis of these tissues, we will determine the key functional properties of the major breast cell populations in BRCA1/2 carriers compared to controls in order to determine the cause of abnormal function within these cell populations. Our preliminary data have revealed novel mechanisms of luminal progenitor (LP) cell regulation that may suggest a practical way to reverse cancer-associated LP deregulation and thereby decrease breast cancer risk. These studies are likely to have near-term impact, identifying new targets for breast cancer prevention for future clinical trials.
Stover, Daniel MD
The host immune system is critical in the control and elimination of tumors in many cancer types. In breast cancer, tumor infiltrating immune cells have been associated with both response to chemotherapy and overall outcome for patients. Understanding what immune cell populations infiltrate tumors may help guide which patients are likely to benefit from chemotherapy and provide targets to improve the efficacy of chemo- and other therapies. Within breast cancer, estrogen receptor (ER)-positive breast cancers comprise the majority of all breast cancers but the role of immune cells remains less well-understood relative to other breast cancer subtypes. We developed evidence that immune cells play a critical role in response to chemotherapy in a subset of patients with ER-positive breast cancers. As a Terri Brodeur Fellow, Dr. Stover will integrate large, publicly available datasets to investigate immune cell signatures in thousands of breast tumors. In parallel, he will work to understand immune cell subsets in breast cancer biopsies of patients on clinical trials of chemotherapy and immune-directed therapies. Ultimately, his goal is to develop biologically rational, immune-based biomarkers to guide therapy, including chemotherapy and immune-directed therapies.
Toska, Eneda PhD
Mutations in the PIK3CA gene are the most frequent genomic alterations in estrogen receptor (ER)-positive breast cancers. One treatment strategy is the use of drugs that inhibit the gene’s signaling pathway – however, many patients eventually become resistant to this type of therapy. Further, P13K signaling pathway inhibition has been shown to increase ER activity, which then increases cells’ dependency on ER and estrogen – fueling growth. However, very little is known about the molecular basis of the crosstalk between the PI3K pathway and ER function. To better understand this relationship, we have identified genes that both contribute to PI3K inhibition resistance and are necessary for the ER-PI3K crosstalk. As a Terri Brodeur research fellow, Dr. Toska will explore these newly identified mechanisms of resistance and examine their role on patient biopsies pre-and-on treatment to PI3K inhibitors. With this in mind, she aims to expose new therapeutic targets that could potentially increase treatment success
Li, Ji, PhD
Basal-like breast tumors comprise a heterogeneous group that accounts for about 15% of all breast cancers. They are highly aggressive and generally fail to respond to targeted therapies. Thus, there is a great need to identify novel vulnerabilities and develop novel therapies for this aggressive breast tumor type. The epithelial-to-mesenchymal transition (EMT) is often reactivated during tumor formation. Compared to other breast cancer subtypes, basal-like breast cancers display the highest degree of mesenchymal and stem-like features, which are responsible for tumor initiation, metastasis and therapeutic resistance. We have recently identified genes that regulate EMT in breast cancer using a genome scale screen and identified several RNA splicing factors that are upregulated in basal-like breast cancers and promote the breast tumor formation. We propose to systematically characterize the role of alternative splicing in breast cancer and EMT using genomic, molecular and cellular biology, and computational approaches, and investigate its role in breast tumor metastasis and therapeutic resistance. These studies may lead to new approaches to treat basal-like/triple negative breast cancers
Meyer, Aaron, PhD
Metastatic spread drives the majority of breast cancer mortality and, to do so, requires tumor cells to both disseminate and avoid clearance by the immune system. Inhibiting TAM receptors has shown promising results in models of breast cancer by blocking tumor cell dissemination, preventing resistance to existing therapies, and relieving immune suppression. Based on these results, the first therapies targeting these receptors are now in early clinical studies. However, a better understanding of when and where these receptors drive breast cancer progression is needed to identify which patients will benefit from these therapies. As a Terri Brodeur Fellow, Dr. Meyer will use a computational model to direct design of new inhibitors for the TAM receptors. Using these well-characterized compounds, he will examine the in vivo effects of inhibiting different TAM receptor complements. By measuring the cellular and molecular consequences of each treatment, and which changes correspond to a therapeutic benefit, he hopes to both develop a clearer picture of when and where these receptors drive breast cancer progression. This information will, in turn, help to address which patients will benefit from these therapies.
Parsons, Heather, MD
This year, breast cancer will claim the lives of more than 500,000 people worldwide. Most of these will be women in whom the disease has spread to the rest of the body, known as metastatic breast cancer. Women living with metastatic breast cancer typically receive ongoing, single-agent treatments that are effective for a while, but at some point, the disease develops resistance, evading a previously effective therapy and growing again. HER2-overexpressing (HER2-positive) breast cancer is a subtype that accounts for 20-25% of breast cancers, and is associated with faster growing tumors, higher rates of recurrence, and higher rates of brain metastases. Though we have effective treatments for HER2-positive metastatic breast cancer, inevitably the disease develops resistance and progresses. Understanding how and why metastatic breast cancer develops resistance is difficult, but is critical to the development of better treatments for women with this disease. Evidence increasingly suggests that tumors evolve genomically over time and in the face of ongoing systemic therapies. A major obstacle to understanding treatment resistance is access to metastatic tumor tissue, as patients with metastatic breast cancer do not typically undergo multiple, sequential biopsies. Both tumor and normal cells shed DNA into the circulation, and even a small amount of circulating tumor DNA (ctDNA) is detectable via next-generation sequencing technologies that are able to “read” the DNA code. As a Terri Brodeur fellow, Dr. Parsons aims to identify, via the ctDNA changes in the tumor, DNA that cause treatment resistance in patients with HER2-positive metastatic breast cancer. She hypothesizes that she will see more of these changes in the ctDNA of patients with metastatic breast cancer who have had extensive treatment than those who have not or those with early-stage breast cancer. These changes may explain why these cancers develop resistance to treatment. By knowing what these changes are, Dr. Parsons aims to enable the development of better treatments for women with HER2-positive metastatic breast cancer. She intends to use the findings to design better studies, and ultimately, treatments for women with metastatic breast cancer. This project has the potential to transform our understanding of metastatic breast cancer, and to significantly advance the use of ctDNA to better understand metastatic cancer.
Dasgupta, Arko, PhD
Breast cancer is a major killer in the United States and metastases are the primary cause of breast cancer-related deaths. Approximately 30% of breast cancer patients will develop metastases during their lifetime. Few prognostic factors predict metastases as well as the presence of dormant disseminated tumor cells (DTCs) – cells that have escaped from the primary breast tumor early in the disease and exist in a dormant state in distant organs until they develop in some patients as overt metastases. Clinical evidence suggests that eradication of DTCs would prevent metastasis, however, currently no therapies specifically target these metastases-initiating cells. Indeed, DTCs are resistant to chemotherapy and other targeted therapies, and very little is known about what enables DTC survival despite multiple rounds of chemotherapy. Breast DTCs reside in a perivascular niche (PVN) – areas within a tissue that are occupied by blood vessels – of distant tissues such as lung, bone marrow, brain, liver and lymph node. Importantly, chemotherapy itself has been show to elicit responses that alter the tumor microenvironment that also contribute to chemo-resistance in other cancers such as prostate cancer. This may be associated with the induction of DNA damage and the consequent change in factors released by blood vessels – a phenomena that remains unexplored in the context of breast DTCs. Preliminary data generated by Dr. Dasgupta suggests that the PVN protect DTCs from chemotherapy. Accordingly, eradicating DTCs for metastasis prevention will require a much deeper understanding the dynamic relationship between DTCs and their microenvironment (PVN).
Sun, Sheng, PhD
The majority of breast cancers express hormone receptors, and therapies that antagonize hormonal signaling via these receptors are the most effective treatments for hormone receptor-positive metastatic breast cancer (HR+ MBC). Unfortunately, for the vast majority of patients with hormonal therapy-refractory MBC, the mechanisms of resistance remain poorly understood. Thus, identifying new mechanisms of hormonal therapy resistance and understanding how to overcome them will have direct and immediate relevance to the therapy of patients with MBC. We have identified novel gene fusions in 14% of patients with HR+ MBC and provided strong evidence that these tumor-specific genetic rearrangements are powerful drivers of treatment resistance and poor outcomes. Successfully tracking and therapeutically targeting these fusions could thus have a major impact on patient outcomes. We hypothesize that patient-derived circulating exosomes (tiny cell-derived vesicles that circulate in the bloodstream) are likely to contain unique nucleic acids and proteins corresponding to the fusions that could potentially serve as novel biomarkers. We propose to credential these patient-specific rearrangements as blood-based markers of disease burden, clinical response and treatment outcome in MBC. This work will pave the way for effective disease monitoring that will facilitate the clinical development of targeted therapeutics to overcome treatment resistance mediated by these genetic drivers.
Waks, Adrienne Gropper, MD
Following many important advances in treating HER2-positive breast cancer over the past two decades, a large majority of patients with non-metastatic HER2-positive tumors are cured with today’s treatments. For this majority of patients who do well in the long-term, we must begin to identify ways to cure HER2-positive breast cancer with less toxic treatments. Modern treatment regimens for stage II and III non-metastatic HER2-positive breast cancer consist of multiple chemotherapy agents plus HER2-directed therapy with trastuzumab (Herceptin, H) and sometimes pertuzumab (Perjeta, P). Scaling back the number of chemotherapy agents used may allow patients to maintain better quality of life while on treatment, as well as decrease the chance of rare but serious chemotherapy complications. As a Terri Brodeur fellow, Dr. Waks plans to conduct a clinical trial investigating a new treatment approach in stage II and III HER2-positive breast cancer, with the goal of allowing select patients to receive less chemotherapy. We know that in patients who receive breast cancer treatment before breast surgery, those who have all cancer eradicated from the breast and lymph nodes at the time of surgery (“pathologic complete response”) have an excellent prognosis. In our clinical trial, patients will be treated before surgery with paclitaxel, trastuzumab, and pertuzumab (“THP”), and those who achieve pathologic complete response at surgery—and have an excellent prognosis on that basis—will go on to receive further HP post-surgery, without any additional chemotherapy. Our primary goal in the trial is to assess the acceptability of this treatment approach to patients and their doctors. We hope that this trial, which is a precursor to a large international trial investigating the same approach, will be a step toward establishing HER2-positive breast cancer treatments that are highly effective for a select patient group, and also maximize patient quality of life.
Garrido-Castro, Ana, MD
Choosing the best treatments for metastatic breast cancer depends increasingly on molecular features, such as tumor subtype. Patients with hormone receptor-positive/HER2-negative breast cancer are typically treated initially with hormonal therapies, and then subsequently with chemotherapy once hormonal therapy loses its
effectiveness. Loss of hormone receptor expression has been described as a mechanism of resistance to hormonal therapy. When this occurs, tumors become hormone receptor-negative and HER2-negative, i.e. triple-negative. It is unknown whether cancers that start out hormone receptor-positive and then become triple-negative (called “subtype switch”) are different than those that remain triple-negative throughout a patient’s disease course. Since treatments depend so heavily on tumor subtype, answering this question could have an immediate impact on patient care.
Metastatic triple-negative breast cancer (mTNBC) remains a clinically unmet need, with a highly aggressive clinical course and shorter average survival compared to patients with other subtypes of metastatic breast cancer. Patients whose tumors are initially hormone receptor-positive/HER2-negative and then lose hormone receptor expression (i.e. become triple-negative) are typically eligible for clinical trials and standard-of-care
therapies focused on mTNBC. However, comparison of tumor biology and clinical outcomes in patients whose tumors are always triple-negative and those that “switch subtype” has not been studied in detail. Preliminary results from tumor DNA analysis presented by Dr. Garrido-Castro at the 2018 San Antonio Breast Cancer
Symposium suggest that primary hormone receptor-positive tumors in patients who later developed mTNBC have similar mutation and gene copy number alterations as primary triple-negative tumors.
In addition, hormone receptor-positive breast cancers are generally considered ̈cold ̈ tumors, characterized by decreased immune cell infiltration and low responsiveness to immunotherapy. It is unclear if hormone receptor loss may induce conversion to an immunologically ̈hot ̈ tumor that is more susceptible to immunotherapy. This would have therapeutic implications given recent evidence supporting the combination of immune checkpoint inhibition and chemotherapy as first-line therapy in patients with mTNBC.
As a Terri Brodeur Breast Cancer Foundation Grant recipient, Dr. Garrido-Castro aims to: a) identify genomic profiles and characteristics of the tumor microenvironment associated with hormone receptor loss, and b)
compare these features across tumors with different levels of hormone receptor expression. We hypothesize that primary hormone receptor-positive tumors in patients who later developed mTNBC harbor intrinsic genomic and immune profiles that are similar to primary triple-negative tumors. To test this, we will integrate cutting-edge technologies (i.e. RNA sequencing, multiplex immunofluorescence, assessment of tumor-infiltrating immune cells) to analyze tumor samples collected at Dana-Farber Cancer Institute and correlate these findings with already generated DNA sequencing data.
Dr. Garrido-Castro received her M.D. from Universidad Autónoma de Madrid (Madrid, Spain) and later completed her training in Medical Oncology at Vall d’Hebron University Hospital in Barcelona, Spain. She joined Dana-Farber Cancer Institute in July 2016 after being selected for the Advanced Fellowship in Breast Oncology Program and as a Research Fellow at Harvard Medical School. She recently joined the Faculty at the Dana-Farber Susan F. Smith Center for Women ́s Cancers and will be appointed Instructor in Medicine at Harvard Medical School.