Sofia Merajver

University of Michigan | U-M · Department of Internal Medicine

Introduction: Treating triple-negative breast cancer (TNBC) is challenging due to the lack of clearly defined and targetable biomarkers, and treatment options become increasingly limited with TNBC brain metastases (BM). Since the brain microenvironment has relatively low lipid availability, breast cancer cells that colonize the brain increase their...

TNBC accounts for 10-20% of total breast cancer cases in the US and is more aggressive, higher grade, and has a poorer prognosis than other forms of breast cancer. TNBC is more likely to metastasize within 3-5 years than other forms of breast cancer and has a median survival of 17.6-21.3 months after metastasis. Advances in immunotherapy are promis...

Using dasatinib linked to E3 ligase ligands, we identified a potent and selective dual Csk/c-Src PROTAC degrader. We then replaced dasatinib the c-Src directed ligand with a conformation-selective analog that stabilizes the aC-helix out conformation of c-Src. Using the C-helix out ligand, we identified a PROTAC that is potent and selective for c-Sr...

146 Background: Lung cancer remains the number one cause of cancer-associated mortality worldwide, with a 10-year survival rate of only 5%. While most lung cancers are smoking related, 25% of non-small cell lung cancer (NSCLC) are diagnosed in patients with little or no smoking history. Fusions involving anaplastic lymphoma kinase (ALK) are the onc...

11 Background: Therapeutic development for BrMets remains a critical need. Our previous work on functional precision medicine using patient-derived xenografts (PDXs) from BrMets suggested that drug sensitivity testing may help prioritize drug selection. However, the time needed to establish PDXs makes the PDX platform less desirable for translation...

Introduction: Human epidermal growth factor receptor 2 positive (HER2+) breast cancer tumors have increased risk of brain metastases at an advanced stage. The brain’s microenvironment is relatively low in lipids; therefore, breast cancer cells that colonize the brain have an increased expression of fatty acid synthesis enzymes. This presents a pote...

Purpose: CNS metastases are associated with decreased survival and quality of life for patients with metastatic breast cancer (MBC). Team-based care can optimize outcomes. IMPACT the Brain is a care coordination program that aims to improve access to team-based care for patients with MBC and CNS metastases. Materials and methods: Patients with M...

Cellular metabolism sits at the forefront of growth and has been identified as an essential element for the progression of cancer. Large-scale chromosomal alterations and mutations incurred by cancerous cells can predispose cancer cells to dysfunctional metabolic programming independent of microenvironmental pressure. Cancer cells are adaptable to...

Introduction: Bladder cancer (BC) is the most frequent urinary system cancer in the US. Neoadjuvant chemotherapy before cystectomy for muscle-invasive BC is standard management, though the absolute survival benefit is small, with many patients progressing during chemotherapy. Identifying therapies with a high probability of specific activity agains...

e18635 Background: Central nervous system (CNS) metastases are associated with decreased quality of life for patients with metastatic breast cancer (MBC). Collecting patient-reported outcome (PRO) data can identify patient needs and inform patient-focused interventions. IMPACT the Brain is a care coordination program that aims to improve access to...

10605 Background: Lynch syndrome (LS) and hereditary breast and ovarian cancer (HBOC) have a population prevalence of 1/279 ¹ and 1/400 ² , respectively. Despite this, >80% of patients referred for cancer genetic counseling report personal or family history of breast cancer ³ . This disparity may be due to increased media attention for HBOC, lower...

47 Background: Central nervous system (CNS) metastases are associated with decreased survival and quality of life for patients with metastatic breast cancer (MBC). Multi-disciplinary care can optimize outcomes. This project aims to improve access to coordinated care for patients with MBC and CNS metastases while assessing patient-reported outcomes...

Central nervous system (CNS) metastases are associated with decreased survival and quality of life for patients with metastatic breast cancer (MBC). Multi-disciplinary care can optimize outcomes. This project aims to improve access to coordinated care for patients with MBC and CNS metastases. Patients with MBC and CNS metastases are referred and of...

10527 Background: Among patients with early-stage breast cancer, approximately 6-10% have a pathogenic germline variant (PGV) conferring inherited cancer predisposition. In contrast, few studies have explored the frequency and types of PGVs identified in patients with metastatic breast cancer (MBC); therefore, additional data is needed. Methods: Fr...

e14003 Background: Brain metastases (BrMet) remain a clinically challenge. There is an increase interest in evaluating the efficiacy of systemic therapy for BrMet. Patient-derived organoids (PDO) and xenografts (PDX) are thought to capture the tumor heterogeneity and molecular alterations of the source tumor, and may be used as ‘avatars’ for therap...

256 Background: The InheRET personal and family health history survey was administered to 384 patients at three Michigan Medicine Clinics (2 primary care (11% of patients) and one breast and ovarian cancer risk clinic (89% of patients)) between October 1, 2018 and May 31, 2019. Since family history alone misses ~30% of those with deleterious germli...

1542 Background: Minority populations experience inequities of access to cancer genetics. We developed and tested an online family history collection and interpretation tool, InheRET, to determine acceptability, validity and utility.Patients are mostly unable to recall accurate family history in clinic and providers have little time to collect the...

The human endogenous retroviruses HERV-K HML-2 have been considered a possible cause of human breast cancer (BrC). A HERV-K HML-2 fully intact provirus Xq21.33 was recently identified in some West African people. We used PCR technology to search for the Xq21.33 provirus in DNA from Nigerian women with BrC and controls. to see if Xq21.33 plays any r...

543 Background: Neoadjuvant chemotherapy prior to radical cystectomy (RC) for muscle-invasive urothelial carcinoma (UCCx) is the standard of care though the absolute survival benefit is small, and some patients progress during chemotherapy. While progress has been made in the prediction of sensitivity to platinum-based chemotherapies, providing mor...

By combining the radial migration assay with injection molded gaskets and a rigid fixture, we have developed a more reliable and sensitive method for measuring radial cell migration. This method is well adapted for use on high throughput automated imaging systems. The use of injection molded gaskets enables low cost replacement of cell wetted compo...

Purpose There is a need for biomarkers of drug efficacy for targeted therapies in triple-negative breast cancer (TNBC). As a step toward this, we identify multi-omic molecular determinants of anti-TNBC efficacy in cell lines for a panel of oncology drugs. Methods Using 23 TNBC cell lines, drug sensitivity scores (DSS3) were determined using a pane...

Increased availability of drug response and genomics data for many tumor cell lines has accelerated the development of pan-cancer prediction models of drug response. However, it is unclear how much between-tissue differences in drug response and molecular characteristics may contribute to pan-cancer predictions. Also unknown is whether the performa...

In breast cancer, tumor hypoxia has been linked to poor prognosis and increased metastasis. Hypoxia activates transcriptional programs in cancer cells that lead to increased motility and invasion, as well as various metabolic changes. One of these metabolic changes, an increase in glycogen metabolism, has been further associated with protection fro...

Metabolic flux technology with the Seahorse bioanalyzer has emerged as a standard technique in cellular metabolism studies, allowing for simultaneous kinetic measurements of respiration and glycolysis. Methods to extend the utility and versatility of the metabolic flux assay would undoubtedly have immediate and wide-reaching impacts. Herein, we des...

Purpose We describe the clinico-pathologic and mammographic characteristics of inflammatory breast cancer (IBC) and non-IBC cases enrolled in a case–control study. Because IBC is a clinico-pathologic entity with rapid appearance of erythema and other signs, its diagnosis is based on clinical observation and thus, by necessity, subjective. Therefore...

Purpose: Long-term treatment of chronic myelogenous leukemia (CML) with the Bcr-Abl inhibitor imatinib, is initially successful but gives rise to several drug-resistant mutations. The most prevalent of these is the T315I ‘gatekeeper’ mutation that is sensitive to the second-line therapy, ponatinib. However, ponatinib causes serious vascular adverse...

Triple negative breast cancer (TNBC) is one of the deadliest forms of breast cancer due to limited treatment options beyond conventional chemotherapy. While making up approximately 10-20% of total breast cancer cases in the US, TNBC carries a serious burden of disease as it tends to be more aggressive, higher grade, and have a poorer prognosis than...

Objective: To investigate subtype-specific risk of germline alleles associated with triple negative breast cancer (TNBC) in African ancestry populations. Background: Breast cancer (BC) mortality is higher in African American (AA) compared to White American (WA) women; this disparity is partly explained by 2-fold higher TNBC incidence. Methods:...

Molecular characteristics that accurately forecast tumor response to drug therapies represent an important target for precision cancer treatment. However, it is not known whether tumor drug response can be predicted in a tissue-agnostic manner or if predictions must be established within historically-defined cancer types and subtypes. To address th...

Inflammatory breast cancer (IBC) is an extremely aggressive and rare form of cancer that disproportionally affects African American and younger women. While IBC represents 1-5% of breast cancers, it accounts for 10% of all breast cancer deaths annually in the United States. We have previously shown that the metabolic characteristics of IBC, specifi...

The high metastatic potential of inflammatory and other aggressive breast cancer is the major determinant of mortality. Recently, it has become clear that signals from the tumor microenvironment (TME) harbor the capacity to enhance cancer cell dissemination. Of the various cells that comprise the TME, macrophages are the most abundant in solid tumo...

Triple negative breast cancer (TNBC) is one of the deadliest forms of breast cancer due to limited treatment options beyond conventional chemotherapy. While making up approximately 10-20% of total breast cancer cases in the US, TNBC carries a serious burden of disease as it tends to be more aggressive, higher grade, and have a poorer prognosis than...

Purpose: Long-term treatment of chronic myelogenous leukemia (CML) with the Bcr-Abl inhibitor imatinib, is initially successful but gives rise to several drug-resistant mutations. The most prevalent of these is the T315I ‘gatekeeper’ mutation that is sensitive to the second-line therapy, ponatinib. However, ponatinib causes serious vascular adverse...

Tumor associated macrophages (TAMs) are increasingly recognized as major contributors to the metastatic progression of breast cancer and enriched levels of TAMs often correlate with poor prognosis. Despite our current advances it remains unclear which subset of M2-like macrophages have the highest capacity to enhance the metastatic program and whic...

1530 Background: Identifying the ~60 million unaffected persons in the US at risk for inherited cancers has the potential to reduce their cancer risk by up to 95%. However, most of these individuals are not identified currently because of multifactorial deficits in the 3-generation pedigree collection in clinical settings. Methods: Here we evaluate...

Brain metastases are the most lethal complication of advanced cancer; therefore, it is critical to identify when a tumor has the potential to metastasize to the brain. There are currently no interventions that shed light on the potential of primary tumors to metastasize to the brain. We constructed and tested a platform to quantitatively profile th...

Background: Breast cancer brain metastasis (BM) is an area of unmet need in metastatic breast cancer patients. Novel therapeutic interventions to help prevent and treat BM are warranted. We conducted integrative molecular profiling of BM and matched primary tumors (PT) using next-generation DNA and RNA sequencing to examine the molecular landscape....

Cancer stem‐like cells (CSCs) have been shown to initiate tumorigenesis and cancer metastasis in many cancer types. Although identification of CSCs through specific marker expression helps define the CSC compartment, it does not directly provide information on how or why this cancer cell subpopulation is more metastatic or tumorigenic. In this stud...

Background and aims Conjunctival squamous cell carcinoma (CSCC) varies in incidence geographically from 0 to 1 case per 100 000 per year globally. Additionally, the incidence of CSCC is known to increase 49% for every 10° decrease in latitude. Since the onset of the AIDS epidemic, there has been a trend of increasing incidence of CSCC in Africa, an...

Increasing use of genetic services (counseling/testing) among young breast cancer survivors (YBCS) can help decrease breast cancer incidence and mortality. The study examined use of genetic services between Black and White/Other YBCS, attitudes and knowledge of breast cancer risk factors, and reasons for disparities in using genetic services. We us...

Background: Population-based incidence rates of breast cancer (BC) that does not express the estrogen receptor (ER), progesterone receptor (PR) or overexpress the human epidermal growth factor 2 HER2/ neu (triple negative breast cancer, TNBC) are higher among Africans compared with white women. However the underlying biologic and genetic difference...

Purpose: Population-based incidence rates of breast cancers that are negative for estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2/ neu (triple-negative breast cancer [TNBC]) are higher among African American (AA) compared with white American (WA) women, and TNBC prevalence is elevated among selected popu...

Overexpression of RhoC protein in breast cancer patients has been linked to increased cancer cell invasion, migration, and metastases. Suppressing RhoC expression in aggressive breast cancer cells using silencing RNA (siRNA) molecules is a viable strategy to inhibit the metastatic spread of breast cancer. In this report, we describe the synthesis o...

Although breast cancer stem cells (BCSCs) display plasticity transitioning between quiescent mesenchymal-like (M) and proliferative epithelial-like (E) states, how this plasticity is regulated by metabolic or oxidative stress remains poorly understood. Here, we show that M- and E-BCSCs rely on distinct metabolic pathways and display markedly differ...

One of the major clinical challenges in breast cancer treatment is the rapid development of resistance to targeted therapies. In light of this, there is significant interest in identifying markers of drug resistance. In particular, markers of drug resistance are sought that can be targeted to overcome acquired drug resistance. To this end, we have...

Background: Population-based incidence rates of breast cancers that are negative for the estrogen receptor (ER), progesterone receptor (PR), HER2/neu triple-negative breast cancer (TNBC) are higher among African American (AA) compared to White American (WA) women, and several studies suggest that TNBC prevalence is increased among selected populati...

RhoC, a member of the Rho GTPase family, has been shown to have a role specifically in facilitating metastasis of breast cancer cells¹, however no conclusive mechanism for how RhoC promotes metastasis currently exists. We demonstrate that CRISPR-Cas9 knockout of RhoC in SUM149 and MDA-MB231 cells results in increased epithelial morphology, cell-cel...

Metastasis from the primary tumor site to the brain is the most lethal complication of advanced breast cancer. There is no translational approach to detect if a primary tumor has brain metastatic potential. This is due to a lack of blood brain barrier (BBB) models that can classify a cells metastatic potential. Moreover, the mechanisms by which cir...

Cancers utilize diverse metabolic pathways to increase survival and proliferation; therefore, the identification of specific metabolic alterations in aggressive triple-negative and inflammatory breast cancers is a compelling avenue for the development of new treatments. The ability to survive and grow in hypoxia is necessary for breast cancer cells...

Inflammatory breast cancer (IBC) is an extremely aggressive and lethal type of cancer due to its ability to rapidly metastasize. Our previous reports have shown that the metabolic characteristics of IBC are altered from those of normal breast epithelial cells. Specifically, the levels of the metabolite N-acetylaspartate (NAA) are very high in the I...

Breast cancer commonly gives rise to lymph node metastases, and it has been suggested that tumor cell migration is facilitated by the generation of new lymphatic vessels, or lymphangiogenesis. Lymphatic endothelial cell hyaluronic acid receptor 1 (LYVE-1) is a hyaluronic acid (HA) receptor commonly used as a lymphatic vessel endothelial marker. LYV...

High-throughput phenotypic screens that incorporate compound biochemical activity annotations are positioned for novel target discovery in cancer. We used machine learning approaches to correlate kinome-wide profiling data of a collection of kinase inhibitors with phenotypic cell proliferation data for the same compounds. We assembled a library of...

Purpose: This study examined clinical breast exam (CBE) and mammography surveillance in long-term young breast cancer survivors (YBCS) and identified barriers and facilitators to cancer surveillance practices. Methods: Data collected with a self-administered survey from a statewide, randomly selected sample of YBCS diagnosed with invasive breast...

Background: Carriers of breast cancer gene (BRCA) mutations are asked to communicate genetic test results to their biological relatives to increase awareness of cancer risk and promote use of genetic services. This process is highly variable from family to family. Interventions that support communication of genetic test results, coping, and offer...

This abstract was withdrawn by the authors.

Breast cancer stem cells (BCSCs) maintain the plasticity to transition between quiescent mesenchymal- (M) and proliferative epithelial-like (E) states, but how this plasticity is regulated under metabolic/oxidative stress is poorly understood. Here, we show that M- and E-BCSCs exhibit markedly different sensitivities to the inhibitors of glycolysis...

The analysis of invading leader cells at the tumor invasion front is of significant interest as these cells may possess a coordinated functional and molecular phenotype which can be targeted for therapy. However, such analyses are currently limited by available technologies. Here, we report a fluidic device for long-term three-dimensional tumoroid...

Defective endocytosis and vesicular trafficking of signaling receptors has recently emerged as a multifaceted hallmark of malignant cells. Clathrin-coated pits (CCPs), the fundamental unit of clathrin-mediated endocytosis, display highly heterogeneous dynamics on the plasma membrane where they can take from 20 seconds to over a minute to form cytos...

To realize the promise of precision medicine, it is important to integrate phenotypic assessment of cell populations to genomic data. The analysis of invading leader cells at the tumor invasion front is of interest as they may be guided by a targetable molecular phenotype. However, there is a lack of suitable platforms on which to analyze the tumor...

Triple negative breast cancers (TNBCs) are especially lethal due to their high metastatic potential and propensity to recur. TNBCs comprise the only subset of breast cancer for which there are no FDA-approved targeted therapies. We have developed a mechanistically novel dual c-Src/p38 inhibitor, UM-164, that has potent in vivo anti-TNBC activity. H...

TNBC is the only subtype of breast cancer for which there are no approved targeted therapies. In the US, its incidence is highest in women with African ancestry (AA); in western sub-Saharan Africa, single-institution studies show that TNBC constitutes 40- 80% of all breast cancers. Given the Caucasian/AA survival disparity in breast cancer, there i...

Breast cancer stem cells (BCSCs) exist in a dynamic equilibrium of mesenchymal- (M) and epithelial-like (E) states that coordinately drive tumorigenesis, metastasis, and treatment resistance. Here, we show that BCSCs in both states display hyperactive aerobic glycolysis or oxidative phosphorylation (OXPHOS), depending on the availability of glucose...

Isolation of specific metabolic alterations in aggressive triple negative and inflammatory breast cancers represents a compelling avenue for the development of treatments for these diseases. The ability of cancer to utilize diverse metabolic pathways to modulate increased survival and proliferation is well established. Indeed, we have previously de...

1101 Background: Population-based incidence rates of breast cancers that are negative for estrogen receptor (ER), progesterone receptor (PR), and HER2/ neu(triple negative breast cancer {TNBC}) are higher among African American (AA) compared to White American (WA) women. Several studies show higher TNBC frequency among selected populations of Afric...

Despite the large number of cargo molecules that traffic through clathrin-coated pits (CCPs), it is not well understood whether signaling receptors activated in cancer, such as epidermal growth factor receptor (EGFR), are regulated through a specific subset of CCPs. The signaling lipid phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3), which...

PurposeBreast cancer, the most common cancer worldwide, is the leading cause of cancer mortality in Ghanaian women. Previous studies find Ghanaian women are diagnosed at a younger age and at more advanced stages (III and IV), and have tumors with characteristics similar to African American women. We sought to remedy gaps in knowledge about breast c...

Background Inflammatory breast cancer (IBC) is a rare, aggressive breast cancer diagnosed clinically by the presence of diffuse erythema, peau d’orange, and edema that arise quickly in the affected breast. This study evaluated the validity of medical records in Gharbiah, Egypt in identifying clinical signs/symptoms of IBC. For 34 IBC cases enrolled...

Purpose: Cancer genetic services (counseling/testing) are recommended for women diagnosed with breast cancer younger than 45 years old (young breast cancer survivors-YBCS) and at-risk relatives. We present recruitment of YBCS, identification and recruitment of at-risk relatives, and YBCS willingness to contact their cancer-free, female relatives....

Phenotypic plasticity is posed to be a vital trait of cancer cells such as circulating tumor cells, allowing them to undergo reversible or irreversible switching between phenotypic states important for tumorigenesis and metastasis. While irreversible phenotypic switching can be detected by studying the genome, reversible phenotypic switching is oft...

The NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling for hereditary cancer syndromes and risk management recommendations for patients who are diagnosed with a syndrome. Guidelines focus on syndromes associated with an increased risk...

The advent of rapid and progressively more affordable sequencing and gene expression studies have spurred research on therapies for cancer targeted to specific gene alterations. With few exceptions, such as those cancers with either a paucity of mutations or major chromosomal rearrangements driving the neoplastic transformation, the approaches base...