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Freedman, Jennifer

Positions:

Assistant Professor in the Department of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2001

Ph.D. — Emory University

Grants:

PC150506: Small molecule targeting of RNA splice variants driving tumor aggressiveness

Administered By
Chemistry
AwardedBy
United States Army Medical Research Acquisition Activity
Role
Collaborator
Start Date
September 30, 2016
End Date
September 29, 2019

Identification of Genetic Determinates for Disparities in African American Patients with Non-Small Cell Lung Cancer

Administered By
Medicine, Medical Oncology
AwardedBy
V Foundation for Cancer Research
Role
Co-Principal Investigator
Start Date
November 01, 2016
End Date
November 01, 2017

Validation and interrogation of differentially expressed and alternatively spliced genes in African American prostate ca

Administered By
Duke Cancer Institute
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 30, 2014
End Date
September 29, 2017

Aptamer Targeted Drug and Toxin Delivery to Prostate Cancer

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Collaborator
Start Date
September 30, 2014
End Date
November 29, 2016
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Publications:

Treatment-related neuroendocrine prostate cancer resulting in Cushing's syndrome.

Here we present, to the best of our knowledge, the first case of a paraneoplastic Cushing's syndrome (hypercortisolism) resulting from treatment-related neuroendocrine prostate cancer - a highly aggressive and difficult disease to treat. A 51-year-old man was started on androgen deprivation therapy after presenting with metastatic prostate cancer, characterized by diffuse osseous metastasis. Shortly thereafter, he developed progressive disease with biopsy proven neuroendocrine prostate cancer as well as symptoms of increased skin pigmentation, hypokalemia, hypertension, hyperglycemia and profound weakness, consistent with ectopic Cushing's syndrome. Molecular analysis of the patient's tumor through RNA sequencing showed high expression of several genes including CHGA, ASCL1, CALCA, HES6, PCSK1, CALCB and INSM1 confirming his neuroendocrine phenotype; elevated POMC expression was found, supporting the diagnosis of ectopic Cushing's syndrome.

Authors
Ramalingam, S; Eisenberg, A; Foo, WC; Freedman, J; Armstrong, AJ; Moss, LG; Harrison, MR
MLA Citation
Ramalingam, S, Eisenberg, A, Foo, WC, Freedman, J, Armstrong, AJ, Moss, LG, and Harrison, MR. "Treatment-related neuroendocrine prostate cancer resulting in Cushing's syndrome." International journal of urology : official journal of the Japanese Urological Association 23.12 (December 2016): 1038-1041.
PMID
27766686
Source
epmc
Published In
International Journal of Urology
Volume
23
Issue
12
Publish Date
2016
Start Page
1038
End Page
1041
DOI
10.1111/iju.13225

Targeted Exome Sequencing of the Cancer Genome in Patients with Very High-risk Bladder Cancer.

We completed targeted exome sequencing of the tumors of 50 patients with pTis-pT4b bladder cancer. Mutations were categorized by type, stratified against previously identified cancer loci in the Catalogue of Somatic Mutations in Cancer and The Cancer Genome Atlas databases, and evaluated in pathway analysis and comutation plots. We analyzed mutation associations with receipt of neoadjuvant chemotherapy, nodal involvement, metastatic disease development, and survival. Compared with The Cancer Genome Atlas, we found higher mutation rates in genes encoding products involved in epigenetic regulation and cell cycle regulation. Of the pathways examined, PI3K/mTOR and Cell Cycle/DNA Repair exhibited the greatest frequencies of mutation. RB1 and TP53, as well as NF1 and PIK3CA were frequently comutated. We identified no association between mutations in specific genes and key clinical outcomes of interest when corrected for multiple testing. Discovery phase analysis of the somatic mutations in 50 high-risk bladder cancer patients revealed novel mutations and mutational patterns, which may be useful for developing targeted therapy regimens or new biomarkers for patients at very high risk of disease metastasis and death.In this report we found known, as well as previously unreported, genetic mutations in the tumors of patients with high-risk bladder cancer. These mutations, if validated, may serve as actionable targets for new trials.

Authors
Longo, T; McGinley, KF; Freedman, JA; Etienne, W; Wu, Y; Sibley, A; Owzar, K; Gresham, J; Moy, C; Szabo, S; Greshock, J; Zhou, H; Bai, Y; Inman, BA
MLA Citation
Longo, T, McGinley, KF, Freedman, JA, Etienne, W, Wu, Y, Sibley, A, Owzar, K, Gresham, J, Moy, C, Szabo, S, Greshock, J, Zhou, H, Bai, Y, and Inman, BA. "Targeted Exome Sequencing of the Cancer Genome in Patients with Very High-risk Bladder Cancer." European urology 70.5 (November 2016): 714-717.
PMID
27520487
Source
epmc
Published In
European Urology
Volume
70
Issue
5
Publish Date
2016
Start Page
714
End Page
717
DOI
10.1016/j.eururo.2016.07.049

Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer.

Treatment with androgen-targeted therapies can induce upregulation of epithelial plasticity pathways. Epithelial plasticity is known to be important for metastatic dissemination and therapeutic resistance. The goal of this study is to elucidate the functional consequence of induced epithelial plasticity on AR regulation during disease progression to identify factors important for treatment-resistant and metastatic prostate cancer. We pinpoint the epithelial plasticity transcription factor, Snail, at the nexus of enzalutamide resistance and prostate cancer metastasis both in preclinical models of prostate cancer and in patients. In patients, Snail expression is associated with Gleason 9-10 high-risk disease and is strongly overexpressed in metastases as compared to localized prostate cancer. Snail expression is also elevated in enzalutamide-resistant prostate cancer cells compared to enzalutamide-sensitive cells, and downregulation of Snail re-sensitizes enzalutamide-resistant cells to enzalutamide. While activation of Snail increases migration and invasion, it is also capable of promoting enzalutamide resistance in enzalutamide-sensitive cells. This Snail-mediated enzalutamide resistance is a consequence of increased full-length AR and AR-V7 expression and nuclear localization. Downregulation of either full-length AR or AR-V7 re-sensitizes cells to enzalutamide in the presence of Snail, thus connecting Snail-induced enzalutamide resistance directly to AR biology. Finally, we demonstrate that Snail is capable of mediating-resistance through AR even in the absence of AR-V7. These findings imply that increased Snail expression during progression to metastatic disease may prime cells for resistance to AR-targeted therapies by promoting AR activity in prostate cancer.

Authors
Ware, KE; Somarelli, JA; Schaeffer, D; Li, J; Zhang, T; Park, S; Patierno, SR; Freedman, J; Foo, W-C; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Ware, KE, Somarelli, JA, Schaeffer, D, Li, J, Zhang, T, Park, S, Patierno, SR, Freedman, J, Foo, W-C, Garcia-Blanco, MA, and Armstrong, AJ. "Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer." Oncotarget 7.31 (August 2016): 50507-50521.
PMID
27409172
Source
epmc
Published In
Oncotarget
Volume
7
Issue
31
Publish Date
2016
Start Page
50507
End Page
50521
DOI
10.18632/oncotarget.10476

Melanoma

Authors
Augustine, CK; Freedman, JA; Beasley, GM; Tyler, DS
MLA Citation
Augustine, CK, Freedman, JA, Beasley, GM, and Tyler, DS. "Melanoma." Genomic and Personalized Medicine 2 (2013): 765-775.
Source
scival
Published In
Genomic and Personalized Medicine
Volume
2
Publish Date
2013
Start Page
765
End Page
775
DOI
10.1016/B978-0-12-382227-7.00066-5

Characterization of an oxaliplatin sensitivity predictor in a preclinical murine model of colorectal cancer.

Despite advances in contemporary chemotherapeutic strategies, long-term survival still remains elusive for patients with metastatic colorectal cancer. A better understanding of the molecular markers of drug sensitivity to match therapy with patient is needed to improve clinical outcomes. In this study, we used in vitro drug sensitivity data from the NCI-60 cell lines together with their Affymetrix microarray data to develop a gene expression signature to predict sensitivity to oxaliplatin. To validate our oxaliplatin sensitivity signature, patient-derived colorectal cancer explants (PDCCE) were developed in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice from resected human colorectal tumors. Analysis of gene expression profiles found similarities between the PDCCEs and their parental human tumors, suggesting their utility to study drug sensitivity in vivo. The oxaliplatin sensitivity signature was then validated in vivo with response data from 14 PDCCEs treated with oxaliplatin and was found to have an accuracy of 92.9% (sensitivity = 87.5%; specificity = 100%). Our findings suggest that PDCCEs can be a novel source to study drug sensitivity in colorectal cancer. Furthermore, genomic-based analysis has the potential to be incorporated into future strategies to optimize individual therapy for patients with metastatic colorectal cancer.

Authors
Kim, MK; Osada, T; Barry, WT; Yang, XY; Freedman, JA; Tsamis, KA; Datto, M; Clary, BM; Clay, T; Morse, MA; Febbo, PG; Lyerly, HK; Hsu, DS
MLA Citation
Kim, MK, Osada, T, Barry, WT, Yang, XY, Freedman, JA, Tsamis, KA, Datto, M, Clary, BM, Clay, T, Morse, MA, Febbo, PG, Lyerly, HK, and Hsu, DS. "Characterization of an oxaliplatin sensitivity predictor in a preclinical murine model of colorectal cancer." Mol Cancer Ther 11.7 (July 2012): 1500-1509.
PMID
22351745
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
11
Issue
7
Publish Date
2012
Start Page
1500
End Page
1509
DOI
10.1158/1535-7163.MCT-11-0937

A methodology for utilization of predictive genomic signatures in FFPE samples.

BACKGROUND: Gene expression signatures developed to measure the activity of oncogenic signaling pathways have been used to dissect the heterogeneity of tumor samples and to predict sensitivity to various cancer drugs that target components of the relevant pathways, thus potentially identifying therapeutic options for subgroups of patients. To facilitate broad use, including in a clinical setting, the ability to generate data from formalin-fixed, paraffin-embedded (FFPE) tissues is essential. METHODS: Patterns of pathway activity in matched fresh-frozen and FFPE xenograft tumor samples were generated using the MessageAmp Premier methodology in combination with assays using Affymetrix arrays. Results generated were compared with those obtained from fresh-frozen samples using a standard Affymetrix assay. In addition, gene expression data from patient matched fresh-frozen and FFPE melanomas were also utilized to evaluate the consistency of predictions of oncogenic signaling pathway status. RESULTS: Significant correlation was observed between pathway activity predictions from paired fresh-frozen and FFPE xenograft tumor samples. In addition, significant concordance of pathway activity predictions was also observed between patient matched fresh-frozen and FFPE melanomas. CONCLUSIONS: Reliable and consistent predictions of oncogenic pathway activities can be obtained from FFPE tumor tissue samples. The ability to reliably utilize FFPE patient tumor tissue samples for genomic analyses will lead to a better understanding of the biology of disease progression and, in the clinical setting, will provide tools to guide the choice of therapeutics to those most likely to be effective in treating a patient's disease.

Authors
Freedman, JA; Augustine, CK; Selim, AM; Holshausen, KC; Wei, Z; Tsamis, KA; Hsu, DS; Dressman, HK; Barry, WT; Tyler, DS; Nevins, JR
MLA Citation
Freedman, JA, Augustine, CK, Selim, AM, Holshausen, KC, Wei, Z, Tsamis, KA, Hsu, DS, Dressman, HK, Barry, WT, Tyler, DS, and Nevins, JR. "A methodology for utilization of predictive genomic signatures in FFPE samples. (Published online)" BMC Med Genomics 4 (July 11, 2011): 58-.
PMID
21745407
Source
pubmed
Published In
BMC Medical Genomics
Volume
4
Publish Date
2011
Start Page
58
DOI
10.1186/1755-8794-4-58

Use of gene expression and pathway signatures to characterize the complexity of human melanoma.

A defining characteristic of most human cancers is heterogeneity, resulting from the somatic acquisition of a complex array of genetic and genomic alterations. Dissecting this heterogeneity is critical to developing an understanding of the underlying mechanisms of disease and to paving the way toward personalized treatments of the disease. We used gene expression data sets from the analysis of primary and metastatic melanomas to develop a molecular description of the heterogeneity that characterizes this disease. Unsupervised hierarchical clustering, gene set enrichment analyses, and pathway activity analyses were used to describe the genetic heterogeneity of melanomas. Patterns of gene expression that revealed two distinct classes of primary melanoma, two distinct classes of in-transit melanoma, and at least three subgroups of metastatic melanoma were identified. Expression signatures developed to predict the status of oncogenic signaling pathways were used to explore the biological basis underlying these differential patterns of expression. This analysis of activities revealed unique pathways that distinguished the primary and metastatic subgroups of melanoma. Distinct patterns of gene expression across primary, in-transit, and metastatic melanomas underline the genetic heterogeneity of this disease. This heterogeneity can be described in terms of deregulation of signaling pathways, thus increasing the knowledge of the biological features underlying individual melanomas and potentially directing therapeutic opportunities to individual patients with melanoma.

Authors
Freedman, JA; Tyler, DS; Nevins, JR; Augustine, CK
MLA Citation
Freedman, JA, Tyler, DS, Nevins, JR, and Augustine, CK. "Use of gene expression and pathway signatures to characterize the complexity of human melanoma." Am J Pathol 178.6 (June 2011): 2513-2522.
PMID
21641377
Source
pubmed
Published In
The American journal of pathology
Volume
178
Issue
6
Publish Date
2011
Start Page
2513
End Page
2522
DOI
10.1016/j.ajpath.2011.02.037

A combinatorial mechanism for determining the specificity of E2F activation and repression.

Various studies have detailed the role of E2F proteins in both transcription activation and repression. Further study has shown that distinct promoter elements, but comprising the same E2F-recognition motif, confer positive or negative E2F control and that this reflects binding of either activator or repressor E2F proteins, respectively. We now show that the specificity of binding of an activator or repressor E2F protein is determined by adjacent sequences that bind a cooperating transcription factor. We propose that the functional E2F element is a module comprising not only the E2F-binding site but also the adjacent site for the cooperating transcription factor.

Authors
Freedman, JA; Chang, JT; Jakoi, L; Nevins, JR
MLA Citation
Freedman, JA, Chang, JT, Jakoi, L, and Nevins, JR. "A combinatorial mechanism for determining the specificity of E2F activation and repression." Oncogene 28.32 (August 13, 2009): 2873-2881.
PMID
19543322
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
28
Issue
32
Publish Date
2009
Start Page
2873
End Page
2881
DOI
10.1038/onc.2009.153

Effects of mismatch repair and Hpr1 on transcription-stimulated mitotic recombination in the yeast Saccharomyces cerevisiae

High levels of transcription driven by the GAL1-10 promoter stimulate mitotic recombination between direct repeats (DR) as well as between substrates positioned on non-homologous chromosomes. When the substrates are on non-homologous chromosomes, transcription stimulates both gene conversion and crossover events, but the degree of the stimulation varies depending on which substrate is highly transcribed. In gene conversion assays where only one of the substrates is highly transcribed, the effect of transcribing the donor versus the recipient allele can be highly asymmetric. We have examined the basis of this asymmetry and demonstrate that it relates to the nature of the mismatch present in recombination intermediates and the presence of the Msh3 mismatch repair (MMR) protein. In addition to examining the asymmetry conferred by donor versus recipient allele transcription, the possible contribution of transcription elongation problems to transcription-stimulated recombination has been examined using hpr1 mutants. Hpr1 is important for efficient elongation through certain sequences, and in hpr1 mutants, elongation problems have been correlated with elevated recombination between direct repeats. As expected, we found that combining loss of Hpr1 with high levels of transcription had very strong synergistic effects on recombination rates between direct repeats. When the substrates were on non-homologous chromosomes, a weaker synergistic interaction between transcription and Hpr1 loss was observed in gene conversion assays, but only an additive relationship was observed in a crossover-specific assay. Although these data support a causal link between transcription elongation problems and elevated recombination rates, they also indicate that high levels of transcription can stimulate recombination by additional mechanisms. © 2004 Elsevier B.V. All rights reserved.

Authors
Freedman, JA; Jinks-Robertson, S
MLA Citation
Freedman, JA, and Jinks-Robertson, S. "Effects of mismatch repair and Hpr1 on transcription-stimulated mitotic recombination in the yeast Saccharomyces cerevisiae." DNA Repair 3.11 (2004): 1437-1446.
PMID
15380099
Source
scival
Published In
DNA Repair
Volume
3
Issue
11
Publish Date
2004
Start Page
1437
End Page
1446
DOI
10.1016/j.dnarep.2004.06.005

Identification of a distinctive mutation spectrum associated with high levels of transcription in yeast

High levels of transcription are associated with increased mutation rates in Saccharomyces cerevisiae, a phenomenon termed transcription-associated mutation (TAM). To obtain insight into the mechanism of TAM, we obtained LYS2 forward mutation spectra under low-versus high-transcription conditions in which LYS2 was expressed from either the low-level pLYS2 promoter or the strong pGAL1-10 promoter, respectively. Because of the large size of the LYS2 locus, forward mutations first were mapped to specific LYS2 subregions, and then those mutations that occurred within a defined 736-bp target region were sequenced. In the low-transcription strain base substitutions comprised the majority (64%) of mutations, whereas short insertion-deletion mutations predominated (56%) in the high-transcription strain. Most notably, deletions of 2 nucleotides (nt) comprised 21% of the mutations in the high-transcription strain, and these events occurred predominantly at 5′-(G/C)AAA-3′ sites. No -2 events were present in the low-transcription spectrum, thus identifying 2-nt deletions as a unique mutational signature for TAM.

Authors
Lippert, MJ; Freedman, JA; Barber, MA; Jinks-Robertson, S
MLA Citation
Lippert, MJ, Freedman, JA, Barber, MA, and Jinks-Robertson, S. "Identification of a distinctive mutation spectrum associated with high levels of transcription in yeast." Molecular and Cellular Biology 24.11 (2004): 4801-4809.
PMID
15143174
Source
scival
Published In
Molecular and Cellular Biology
Volume
24
Issue
11
Publish Date
2004
Start Page
4801
End Page
4809
DOI
10.1128/MCB.24.11.4801-4809.2004

Genetic requirements for spontaneous and transcription-stimulated mitotic recombination in Saccharomyces cerevisiae

The genetic requirements for spontaneous and transcription-stimulated mitotic recombination were determined using a recombination system that employs heterochromosomal lys2 substrates that can recombine only by crossover or only by gene conversion. The substrates were fused either to a constitutive low-level promoter (pLYS) or to a highly inducible promoter (pGAL). In the case of the "conversion-only" substrates the use of heterologous promoters allowed either the donor or the recipient allele to be highly transcribed. Transcription of the donor allele stimulated gene conversions in rad50, rad51, rad54, and rad59 mutants, but not in rad52, rad55, and rad57 mutants. In contrast, transcription of the recipient allele stimulated gene conversions in rad50, rad51, rad54, rad55, rad57, and rad59 mutants, but not in rad52 mutants. Finally, transcription stimulated crossovers in rad50, rad54, and rad59 mutants, but not in rad51, rad52, rad55, rad57 mutants. These data are considered in relation to previously proposed molecular mechanisms of transcription-stimulated recombination and in relation to the roles of the recombination proteins.

Authors
Freedman, JA; Jinks-Robertson, S
MLA Citation
Freedman, JA, and Jinks-Robertson, S. "Genetic requirements for spontaneous and transcription-stimulated mitotic recombination in Saccharomyces cerevisiae." Genetics 162.1 (2002): 15-27.
PMID
12242220
Source
scival
Published In
Genetics
Volume
162
Issue
1
Publish Date
2002
Start Page
15
End Page
27

polychaetoid is required to restrict segregation of sensory organ precursors from proneural clusters in Drosophila

Reduction of wild-type activity of the polychaetoid (pyd) gene results in formation of extra mechanosensory bristles on the head and notum of adult Drosophila. Loss of pyd function results in decreased ability to restrict sensory organ precursor (SOP) formation to a single cell per proneural cluster. Although the initial proneural cluster pattern of achaete expression is not altered in pyd mutants, extra cells within proneural clusters express the high levels of achaete characteristic of SOPs. This observation suggests that pyd+ functions as a negative regulator of achaete-scute complex expression within the proneural cluster. Synergistic interactions between pyd and Notch, Delta and extramacrochaetae mutations support this model. We also demonstrate that pyd is required for normal eye development.

Authors
Chen, C-M; Freedman, JA; Jr, DRB; Manning, SD; Giep, SN; Steiner, J; Ellis, HM
MLA Citation
Chen, C-M, Freedman, JA, Jr, DRB, Manning, SD, Giep, SN, Steiner, J, and Ellis, HM. "polychaetoid is required to restrict segregation of sensory organ precursors from proneural clusters in Drosophila." Mechanisms of Development 57.2 (1996): 215-227.
PMID
8843398
Source
scival
Published In
Mechanisms of Development
Volume
57
Issue
2
Publish Date
1996
Start Page
215
End Page
227
DOI
10.1016/0925-4773(96)00548-5
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