Jennifer Freedman

Positions:

Assistant Professor in Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2001

Emory University

Grants:

Publications:

Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer.

Clinical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of the newly cloned AA-enriched variant, PIK3CD-S, in EA PCa cell lines enhances AKT/mTOR signalling and increases proliferative and invasive capacity in vitro and confers resistance to selective PI3Kδ inhibitor, CAL-101 (idelalisib), in mouse xenograft models. High PIK3CD-S expression in PCa specimens associates with poor survival. These results highlight the potential of RNA splice variants to serve as novel biomarkers and molecular targets for developmental therapeutics in aggressive PCa.
Authors
Wang, B-D; Ceniccola, K; Hwang, S; Andrawis, R; Horvath, A; Freedman, JA; Olender, J; Knapp, S; Ching, T; Garmire, L; Patel, V; Garcia-Blanco, MA; Patierno, SR; Lee, NH
MLA Citation
Wang, Bi-Dar, et al. “Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer..” Nat Commun, vol. 8, June 2017. Pubmed, doi:10.1038/ncomms15921.
URI
https://scholars.duke.edu/individual/pub1264786
PMID
28665395
Source
pubmed
Published In
Nature Communications
Volume
8
Published Date
Start Page
15921
DOI
10.1038/ncomms15921

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, Sundhar, et al. “Treatment-related neuroendocrine prostate cancer resulting in Cushing's syndrome..” Int J Urol, vol. 23, no. 12, Dec. 2016, pp. 1038–41. Pubmed, doi:10.1111/iju.13225.
URI
https://scholars.duke.edu/individual/pub1150328
PMID
27766686
Source
pubmed
Published In
Int J Urol
Volume
23
Published Date
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. PATIENT SUMMARY: 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, Thomas, et al. “Targeted Exome Sequencing of the Cancer Genome in Patients with Very High-risk Bladder Cancer..” Eur Urol, vol. 70, no. 5, Nov. 2016, pp. 714–17. Pubmed, doi:10.1016/j.eururo.2016.07.049.
URI
https://scholars.duke.edu/individual/pub1140005
PMID
27520487
Source
pubmed
Published In
Eur Urol
Volume
70
Published Date
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, Kathryn E., et al. “Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer..” Oncotarget, vol. 7, no. 31, Aug. 2016, pp. 50507–21. Pubmed, doi:10.18632/oncotarget.10476.
URI
https://scholars.duke.edu/individual/pub1137904
PMID
27409172
Source
pubmed
Published In
Oncotarget
Volume
7
Published Date
Start Page
50507
End Page
50521
DOI
10.18632/oncotarget.10476

Melanoma

Authors
Augustine, CK; Freedman, JA; Beasley, GM; Tyler, DS
MLA Citation
Augustine, C. K., et al. Melanoma. Vol. 2, Aug. 2013, pp. 765–75. Scopus, doi:10.1016/B978-0-12-382227-7.00066-5.
URI
https://scholars.duke.edu/individual/pub967715
Source
scopus
Volume
2
Published Date
Start Page
765
End Page
775
DOI
10.1016/B978-0-12-382227-7.00066-5