I am a Bentson Translational Research Fellow in the Department of Human Oncology. The study of cancer biology is my passion, and I am dedicated to basic science research that will hopefully improve the care of cancer patients. As an undergraduate, I studied the role of inflammation in lung cancer. In graduate school, I established and characterized a model of cardiac muscle atrophy due to cancer. Throughout medical school, I loved caring for cancer patients, which led me to specialize in radiation oncology. I was fortunate to receive entry into the B. Leonard Holman Research pathway during residency. I performed RNA sequencing of cervical tumors before and during chemoradiation therapy, which provided novel insight into how these tumors respond to treatment and what factors may be involved in treatment resistance. I am continually inspired by my patients, and my goal is to continue research that can be translated to the clinic with the hope of improving patient outcomes.
My main interest is in Human Papilloma Virus (HPV) induced cancers, such as cervical and head and neck cancer. Specifically, I am interested in how the virus hijacks the host cell and how this may contribute to sensitivity to radiation therapy and how this affects the immune response to the tumor. My ultimate goal is to be an independent investigator with my own laboratory that focuses on HPV-induced cancers, while caring for patients afflicted with this disease.
Resident, Washington University in St. Louis, Radiation Oncology (2018)
Intern, St. Joseph Hospital, Internal Medicine (2014)
MD, University of Colorado, (2013)
PhD, University of Colorado Boulder, Molecular Biology (2011)
BS, University of Texas at Austin, Biochemistry (2002)
Bentson Translational Research Fellow, Department of Human Oncology (2018)
Selected Honors and Awards
RSNA Resident Research Grant (2016-2017)
B. Leonard Holman Research Pathway recipient (2015-2017)
NHLBI Pre-Doctoral T32 Award (2008-2011)
American Association of University Women Scholarship (2010)
American Heart Association Pre-Doctoral Fellowship (2007-2009)
Dow Chemical Centennial Endowed Presidential Scholarship (2002)
Boards, Advisory Committees and Professional Organizations
American Society for Radiation Oncology (ASTRO), 2014-pres.
Radiation Research Society (RRS), 2016-pres.
Radiological Society of North America (RSNA), 2016-pres.
American Association for Cancer Research (AACR), 2017-pres.
American Society of Clinical Oncology (ASCO), 2018-pres.
Head & Neck Cancer and Cervical Cancer
Chromosomal instability as a potential mechanism and marker of radiation sensitivity in head and neck cancer.
Human Papilloma Virus (HPV) is the main cause of cervical and oropharyngeal cancers. I am studying how chromosomal instability modulates radiation response in HPV-positive and HPV-negative head and neck cancers and how HPV affects the immune response to the tumor.
Head and neck cancer is the sixth most common cancer worldwide. Human Papilloma Virus (HPV) is recognized as a significant cause of head and neck cancer and represents a unique clinical entity. Chromosomal Instability (CIN) is an ongoing rate of missegregation events over the course of multiple cell divisions, and is common in human tumors. Our laboratory and others have shown that combining two independent insults that each cause low CIN results in high CIN, which leads to cell death and tumor suppression. Ionizing radiation and HPV can each induce low CIN, thus we hypothesize that low CIN in tumors prior to treatment sensitizes head and neck cancer cells to radiation therapy. We propose to test this in vitro and in vivo by creating isogenic chromosomally stable and unstable HPV-positive and HPV-negative cell lines.
Many cell types sense exogenous DNA through the cytosolic DNA receptor GMP-AMP synthase (cGAS), which produces a second messenger cGAMP which activates STING, and ultimately results in a type I interferon immune response. Cells utilize this pathway to protect the host from viral and bacterial infection as well as from genomic instability, which can also cause cytosolic DNA. Many cancer cells have lost this pathway to avoid immune detection and aid in their survival. I am interested in determining if cancers caused by Human Papilloma Virus (HPV) have differential activation of the cGAS/STING pathway at baseline and in response to radiation compared to HPV negative cancers, and whether this affects the immune response to the tumor. Using this information, I hope to gain insight into the differential outcomes of HPV-positive versus negative tumors in order to improve the treatment response of HPV-negative cancers and hopefully increase patient survival.
Intensity modulated radiation therapy and surgery for Management of Retroperitoneal Sarcomas: a single-institution experience. Radiat Oncol
Cosper PF, Olsen J, DeWees T, Van Tine BA, Hawkins W, Michalski J, Zoberi I
2017 Dec 08; 12 (1): 198
BACKGROUND: Peri-operative radiation of retroperitoneal sarcomas (RPS) is an important component of multidisciplinary treatment. All retrospective series thus far included patients treated with older radiation therapy (RT) techniques including 2D and 3DRT. Intensity modulated radiation therapy (IMRT) allows for selective dose escalation while sparing adjacent organs. We therefore report the first series of patients with RPS treated solely with IMRT, surgery and chemotherapy. We hypothesized that IMRT would permit safe dose escalation and superior rates of local control (LC) in this high-risk patient population.
METHODS: Thirty patients with RPS treated with curative intent between 2006 and 2015 were included in this retrospective study. RT was administered either pre- or post-operatively and IMRT was used in all patients. Statistical comparisons, LC, distant metastasis (DM), and overall survival (OS) were calculated by Kaplan-Meier analysis and univariate Cox regression.
RESULTS: Median follow-up time after completion of RT was 36 months (range 1.4-112). Median tumor size was 14 cm (range 3.6 - 28 cm). The most prevalent histologies were liposarcoma in 10 (33%) patients and leiomyosarcoma in 10 (33%) with 21 patients (70%) having high-grade disease. Twenty-eight (93%) patients had surgical resection with 47% having positive margins. Chemotherapy was administered in 9 (30%) patients. RT was delivered pre-operatively in 11 (37%) patients, and post-operatively in 19 (63%) with 60% of patients receiving a simultaneous integrated boost. Pre-operative median RT dose to the high-risk area was 55 Gy (range, 43-66 Gy) while median post-operative dose was 60.4 Gy (range, 45-66.6 Gy). There was one acute grade 3 and one late grade 3 toxicity and no grade 4 or 5 toxicities. Three year actuarial LC, freedom from DM, and OS rates were 84%, 64%, and 68% respectively. Positive surgical margins were associated with a higher risk of local recurrence (p = 0.02) and decreased OS (p = 0.04). Pre-operative RT was associated with improved LC (p = 0.1) with a 5-year actuarial LC of 100%. Administration of chemotherapy, timing of RT, histology or grade was not predictive of OS.
CONCLUSIONS: Patients with RPS treated with peri-operative IMRT at our institution had excellent local control and low incidences of toxicity.View details for PubMedID 29216884
Neoadjuvant Ifosfamide and Epirubicin in the Treatment of Malignant Peripheral Nerve Sheath Tumors. Sarcoma
Hirbe AC, Cosper PF, Dahiya S, Van Tine BA
2017; 2017: 3761292
Background and Objectives. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with poor overall survival. Response to chemotherapy has been debated for these tumors. Methods. We performed a retrospective analysis of the patients at our institution with a biopsy-proven diagnosis of MPNST that underwent neoadjuvant chemotherapy prior to surgery. Results. We retrospectively identified five patients who received neoadjuvant chemotherapy with epirubicin and ifosfamide that demonstrated a 30% reduction in tumor growth and a 60% response rate by RECIST criteria. Additionally, a metabolic response was observed in all three patients who received serial PET scans during neoadjuvant treatment. The clinical benefit rate, which includes stable disease, was 100%. Conclusions. Our data suggest that MPNSTs do respond to epirubicin and ifosfamide based chemotherapy and prospective studies are warranted to further define the clinical benefit.View details for PubMedID 28546782
Prospective analysis of toxicity in patients treated with strut-adjusted volume implant for early-stage breast cancer. Brachytherapy
Rehman S, Agarwal R, Ochoa L, Cosper P, Zoberi J, Cyr A, Margenthaler J, Thomas M, Zoberi I
2016 Sep-Oct; 15 (5): 625-30
PURPOSE: We report the toxicity of patients treated with strut-adjusted volume implant (SAVI) for accelerated partial breast irradiation treated at our institution.
METHODS AND MATERIALS: Patients treated from January 2013 to July 2015 with SAVI planned for 10 b.i.d. fractions for a total dose of 34 Gy were included. Acute and late toxicities were prospectively collected on patients in followup and graded by the Common Terminology Criteria for Adverse Events, version 4.0.
RESULTS: A total of 132 patients were included, with 1 patient having synchronous breast cancer treated in each breast. Median followup was 20.0 months (range, 2.7-37.4 months). The median age at diagnosis was 61 years (range, 41-83 years). Forty-two lesions (32%) were in situ, 88 lesions (66%) were Stage 1, and 3 (2%) lesions were Stage 2. The median planning target volume was 58.2 cc (range, 24.2-109.9 cc), median V150 was 26.3 cc (range, 11.5-47.5 cc), and median V200 was 13.0 cc (range, 6.3-26.1 cc). On a pain scale of 0-10 (10 = worst pain), pain was worst on Day 2 of treatment, with an average score of 0.46. There was one acute skin infection; there were three late skin infections, two of which was Grade 3. Other late toxicities were Grade 1 or 2: hyperpigmentation (44%), telangiectasia (0.8%), seroma (9%), fat necrosis (5%), and fibrosis (12%). Crude local recurrence rate was 4%.
CONCLUSION: SAVI is a safe treatment option for patients who are candidates for accelerated partial breast irradiation. Local control seems to be excellent, but longer followup is needed.View details for PubMedID 27263058
Interferon-γ causes cardiac myocyte atrophy via selective degradation of myosin heavy chain in a model of chronic myocarditis. Am J Pathol
Cosper PF, Harvey PA, Leinwand LA
2012 Dec; 181 (6): 2038-46
Interferon-γ (IFN-γ), a proinflammatory cytokine, has been implicated in the pathogenesis of a number of forms of heart disease including myocarditis and congestive heart failure. In fact, overexpression of IFN-γ in mice causes dilated cardiomyopathy. However, the direct effects of IFN-γ on cardiac myocytes and the mechanism by which it causes cardiac dysfunction have not been described. Here, we present the molecular pathology of IFN-γ exposure and its effect on myofibrillar proteins in isolated neonatal rat ventricular myocytes. Treatment with IFN-γ caused cardiac myocyte atrophy attributable to a specific decrease in myosin heavy chain protein. This selective degradation of myosin heavy chain was not accompanied by a decrease in total protein synthesis or by an increase in total protein degradation. IFN-γ increased both proteasome and immunoproteasome activity in cardiac myocytes and their inhibition blocked myosin heavy chain loss and myocyte atrophy, whereas inhibition of the lysosome or autophagosome did not. Collectively, these results provide a mechanism by which IFN-γ causes cardiac pathology in the setting of chronic inflammatory diseases.View details for PubMedID 23058369
Myosin heavy chain is not selectively decreased in murine cancer cachexia. Int J Cancer
Cosper PF, Leinwand LA
2012 Jun 01; 130 (11): 2722-7
Cachexia is a severe muscle-wasting syndrome associated with several chronic diseases such as cancer and AIDS. Muscle mass loss significantly decreases prognosis and survival. The mechanisms of muscle atrophy and the specific proteins targeted for degradation have been intensely studied and are potential therapeutic targets. Published reports that myosin heavy chain (MyHC), the most abundant protein by mass in skeletal muscle, is selectively targeted for degradation in cancer cachexia remain controversial. Here we show that the results of previous studies showing a selective decrease in MyHC are likely an artifact resulting from muscle lysis methods which do not solubilize myosin out of myofibrils. We show that MyHC decreases in parallel with other myofibrillar proteins in cachectic skeletal muscle, which has mechanistic and therapeutic implications. These findings should lead to mechanistic insight into the stoichiometry of sarcomeric disassembly and degradation during cancer cachexia.View details for PubMedID 21796617
Cancer causes cardiac atrophy and autophagy in a sexually dimorphic manner. Cancer Res
Cosper PF, Leinwand LA
2011 Mar 01; 71 (5): 1710-20
Approximately one-third of cancer deaths are caused by cachexia, a severe form of skeletal muscle and adipose tissue wasting that affects men more than women. The heart also undergoes atrophy in cancer patients, but the mechanisms and the basis for apparent sex differences are unclear. In a mouse colon-adenocarcinoma model, cancer causes a loss of cardiac mass due to a decrease in cardiac myocyte size that is associated with reduced levels of all sarcomeric proteins. Unlike skeletal muscle cachexia, atrophic hearts do not upregulate the ubiquitin-proteasome system or its activity but increase autophagy. Thus, cancer causes cardiac atrophy by a mechanism distinct from that in skeletal muscle. Male tumor-bearing mice have a more severe phenotype than females, including greater cardiac mass loss and mortality, a more robust pro-inflammatory response to the tumor, and greater cardiac autophagy. In females, estrogen protects against cancer-induced cardiac atrophy and body weight loss by signaling through its receptor. Sex differences in cardiac atrophy need to be considered during the treatment of patients suffering from chemotherapy-induced cardiomyopathy to prevent exacerbation of cardiac dysfunction.View details for PubMedID 21163868
A comparison of oral and transdermal short-term estrogen therapy in postmenopausal women with metabolic syndrome. Fertil Steril
Chu MC, Cosper P, Nakhuda GS, Lobo RA
2006 Dec; 86 (6): 1669-75
OBJECTIVE: To determine whether it would be preferable to prescribe oral or transdermal estrogen to symptomatic postmenopausal women with metabolic syndrome (MBS).
DESIGN: Prospective, randomized study.
SETTING: Academic medical center.
PATIENT(S): Fifty obese postmenopausal women with MBS.
INTERVENTION(S): Women were randomized to receive either oral E(2) (oE(2), 1 mg/d) or transdermal E(2) (tE(2), 0.05 mg/d) for 3 months. Fasting blood was obtained before and after treatment for glucose, insulin, lipid profiles, the adipocytokines (adiponectin, leptin, and resistin), and a gastric peptide (ghrelin). In addition, a 75-g 2-hour oral glucose-tolerance and intravenous insulin-tolerance tests were performed before and after E(2).
MAIN OUTCOME MEASURE(S): Changes in parameters of insulin resistance (IR), lipid profiles, and adipocytokine levels.
RESULT(S): Mean serum concentrations of E(2) in women using oE(2) and tE(2) were 39.1 +/- 5.6 and 49.2 +/- 28.6 pg/mL, respectively. After oE(2), there was a statistically significant worsening of IR markers, including an increase in baseline insulin (15.28 +/- 1.27 to 22.02 +/- 2.40 microU/mL), a reduction in quantitative insulin-sensitivity check index (0.3177 +/- 0.0043 to 0.2977 +/- 0.0057), and an increase in homeostasis model assessment (3.96 +/- 0.38 to 8.59 +/- 2.08). The only significant change in the lipid profile was an increase in high-density-lipoprotein cholesterol (50.46 +/- 2.34 vs. 55.08 +/- 2.51 mg/dL). Leptin levels increased (81.43 +/- 7.87 ng/mL to 94.10 +/- 6.56 ng/mL), and adiponectin decreased nonsignificantly, resulting in an increased leptin-adiponectin ratio (12.56 +/- 1.70 to 15.86 +/- 2.24); resistin levels increased (9.37 +/- 1.09 ng/mL to 11.72 +/- 1.10 ng/mL); and baseline ghrelin levels decreased (701.64 +/- 59.79 pg/mL to 581.72 +/- 36.07 pg/mL). After tE(2), no significant changes in IR parameters occurred, except for a decrease in glucose-insulin ratio. There were no changes in lipid parameters. Leptin did not change (72.7 +/- 9.3 ng/mL to 78.8 +/- 7.9 ng/mL), whereas adiponectin levels showed statistically significant increase (7.97 +/- 0.7 microg/mL vs. 9.96 +/- 1.1 microg/mL), with no change in the leptin-adiponectin ratio. Resistin levels did not change significantly, and ghrelin levels decreased (888.52 +/- 109.98 pg/mL vs. 579.04 +/- 39.30 pg/mL).
CONCLUSION(S): This short-term study suggests that oral E(2) may worsen IR and adipocytokine parameters, worsening cardiovascular risk. Transdermal E(2) had minimal effects on IR and resulted in higher adiponectin. Although these data may not reflect alterations that occur with estrogen therapy in more metabolically normal postmenopausal women or with longer term therapy, the findings suggest that tE(2) may be a preferable treatment for obese women with MBS. Long-term studies are needed to make any recommendations.View details for PubMedID 17074346
Insulin resistance in postmenopausal women with metabolic syndrome and the measurements of adiponectin, leptin, resistin, and ghrelin. Am J Obstet Gynecol
Chu MC, Cosper P, Orio F, Carmina E, Lobo RA
2006 Jan; 194 (1): 100-4
OBJECTIVE: Metabolic syndrome (MBS) is a significant health care problem in postmenopausal women and is driven largely by obesity. We wished to assess the prevalence of insulin resistance (IR), diagnosed using practical methods, and whether several adipocyte factors (adiponectin, leptin, resistin) or the gastric peptide ghrelin, associated with cardiovascular risk, might be abnormal and may relate to IR.
STUDY DESIGN: We evaluated 37 obese postmenopausal women with MBS and 34 matched obese premenopausal controls, as well as 14 non-obese premenopausal controls. We measured fasting glucose and insulin, performed 75 g 2 hr oral glucose tolerance and intravenous insulin tolerance tests to assess IR, and measured fasting lipids, adiponectin, leptin, resistin and ghrelin.
RESULTS: The kinetic decline in glucose after insulin (kITT) as a marker of IR was the most frequently abnormal test (abnormal in 81%), with QUICKI, HOMA, and a modification of the Matsuda-DeFronzo index (ISIM) abnormal in 76, 73, and 68%, respectively. The GIR was abnormal in only 35% of subjects. Leptin and resistin were elevated and adiponectin and ghrelin were decreased in the postmenopausal women, compared to both groups of premenopausal controls. BMI correlated strongly with markers of insulin resistance as well as adipocytokine values. After controlling for BMI, only leptin was predictive of ISIM.
CONCLUSION: Being overweight after menopause results in worsening IR and elevations in adipocytokine levels. While BMI is the most important factor, abnormal adipocytokine secretion may enhance IR and increase cardiovascular risk in postmenopausal women.View details for PubMedID 16389017
Cytokines differentially regulate the synthesis of prostanoid and nitric oxide mediators in tumorigenic versus non-tumorigenic mouse lung epithelial cell lines. Carcinogenesis
Dwyer-Nield LD, Srebernak MC, Barrett BS, Ahn J, Cosper P, Meyer AM, Kisley LR, Bauer AK, Thompson DC, Malkinson AM
2005 Jul; 26 (7): 1196-206
Studies using transgenic and knockout mice have demonstrated that particular cytokines influence lung tumor growth and identified prostaglandin E2 (PGE2), prostacyclin (PGI2) and nitric oxide (NO) as critical mediators of this process. PGE2 and NO were pro-tumorigenic while PGI2 was antitumorigenic. We describe herein an in vitro experimental approach to examine interactions among cytokines, prostaglandins (PGs) and NO. PGE2, PGI2, and NO levels were assayed in culture media from non-tumorigenic mouse lung epithelial cell lines, their spontaneous transformants and mouse lung tumor-derived cell lines, before or after exposure to the cytokines TNFalpha, IFNgamma and IL1beta, alone and in combination. More PGE2 than PGI2 was produced by neoplastic cells, while the opposite was observed in non-tumorigenic lines. Cytokine exposure magnified the extent of these differential concentrations. The PGE2 to PGI2 ratio was also greater in chemically-induced mouse lung tumors than in adjacent tissue or control lungs, supporting the physiological relevance of this in vitro model. Expression of PG biosynthetic enzymes in these cell lines correlated with production of the corresponding PGs. Cytokine treatment enhanced NO production by inducing the inflammation-associated biosynthetic enzyme, inducible NO synthase (iNOS), but this did not correlate with the neoplastic status of cells. Inhibition of iNOS or cyclooxygenase 2 activity using aminoguanidine or NS-398 respectively, demonstrated that NO did not affect PG production nor did PGs influence NO production. Since lack of iNOS inhibits mouse lung tumor formation, we propose that this is independent of any modulation of PG synthesis in epithelial cells. The similar normal/neoplastic trends in PGE2 to PGI2 ratios both in vitro and in vivo, together with an amplification of this difference upon cytokine exposure, are consistent with the hypothesis that cytokines released during inflammation exacerbate differences in the behavior of neoplastic and normal lung cells.View details for PubMedID 15746162
Relative amounts of antagonistic splicing factors, hnRNP A1 and ASF/SF2, change during neoplastic lung growth: implications for pre-mRNA processing. Mol Carcinog
Zerbe LK, Pino I, Pio R, Cosper PF, Dwyer-Nield LD, Meyer AM, Port JD, Montuenga LM, Malkinson AM
2004 Dec; 41 (4): 187-96
Pre-mRNA processing is an important mechanism for globally modifying cellular protein composition during tumorigenesis. To understand this process during lung cancer, expression of two key pre-mRNA alternative splicing factors was compared in a mouse model of early lung carcinogenesis and during regenerative growth following reversible lung injury. Heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and alternative splicing factor/splicing factor 2 (ASF/SF2) act antagonistically to modulate splice site selection. Both hnRNP A1 and ASF/SF2 contents rose in adenomas and during injury-induced hyperplasia compared to control lungs, as measured by immunoblotting. While both proteins increased similarly during compensatory hyperplasia, hnRNP A1 increased to a much greater extent than ASF/SF2 in tumors, resulting in a 6-fold increase of the hnRNP A1 to ASF/SF2 ratio. Immunohistochemical analysis showed that hnRNP A1 localized exclusively within tumor nuclei, while ASF/SF2 appeared in cytoplasm and/or nuclei, depending on the growth pattern of the tumor cells. We also demonstrated cancer-associated changes in the pre-mRNA alternative splicing of CD44, a membrane glycoprotein involved in cell-cell and cell-extracellular matrix interactions. hnRNP A1 and ASF/SF2 expression is thus differentially altered in neoplastic lung cells by mechanisms that do not strictly arise from increased cell division. These changes are influenced by tumor histology and may be associated with production of variant CD44 mRNA isoforms.View details for PubMedID 15390079
Pippa Cosper, MD, PhD1111 Highland Avenue,
WIMR I 6128
Madison, WI 53703