Godwin Laboratory

Andrew K. Godwin, Ph.D., is the Chancellors Distinguished Chair in Biomedical Sciences endowed Professor and the Director of Molecular Oncology at KUMC. He serves as the founding director the Clinical Molecular Oncology Laboratory (CMOL), a CLIA-certified, CAP-accredited molecular diagnostics laboratory and supports the precision medicine initiative for the KU Health System. He was recruited to KUMC as the Associate Director for Translational Research for the Cancer Center in November 2010 and his engaged participation as a member of the Cancer Center's leadership team helped led to NCI-designation for the first time in 2012, and resulted in him being promoted to Deputy Director in 2013.

Dr. Godwin also serves as the Director of the KUCC's Biospecimen Repository Core Facility as well as the Scientific Director for the Biomarker Discovery Laboratory (BDL). He was named a Kansas Bioscience Authority Eminent Scholar in 2010 and the Biorepository Coordinator for the HICTR Translational Technologies Resource Center in 2011. His contributions towards education and training was recognized when he was presented the KUMC School of Medicine Achievement Award for Mentoring Post-Docs in 2014 and the KU Medical Center's Faculty Investigator Research Award in 2015.

Dr. Godwin is a leader in the field of translational research and precision medicine, and his laboratories at KUMC continue to focus on various aspects of both basic and translational research. He is a NCI funded investigator (continuously since 1993) and a highly published (>380 manuscripts and scholarly review articles) and cited (>33,000; h-index of 96) scientist. Dr. Godwin is internationally recognized for his molecular biology/genetic studies of cancers including, sarcoma, breast and ovarian, and his efforts to help bridge the gap between basic and clinical science in order to improve patient care. Through the CMOL and BDL, Godwin's group continues to support the development and advancement of rationally designed therapeutic strategies to improve the options for patient treated at the KU Cancer Center.

He is a member of multiple disease-working groups for The Cancer Genome Atlas (TCGA), the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), an international group studying large cohorts of BRCA1/2 mutation carriers for genetic modifiers of breast cancer risk, the Early Detection Research Network (EDRN) for >12 years, and the Early Therapeutics and Rare Cancers Committee and of the Breast Translational Medicine Working Group of the Southwest Oncology Group (SWOG). His research programs continue to focus on various aspects of both basic and translational research, with an emphasis on early detection of cancer, predictive and prognostic biomarkers, liquid biopsies based on extracellular vesicles (e.g., exosomes), molecular therapeutics, companion diagnostics, clinical trials, and biosample ascertainment.

A complete list of Dr. Godwin's publications can be found at the links below. http://scholar.google.com/citations?user=fXDESs0AAAAJ&hl=en&authuser=1 or http://www.ncbi.nlm.nih.gov/sites/myncbi/andrew.godwin.1/bibliography/41140450/public/?sort=date&direction=ascending

Ongoing efforts in Godwin's Research Program which include scientists at all levels of experience.

Ovarian Oncogenesis

Dr. Godwin became interested early in his career in the field of ovarian cancer through early studies of cancer genetics and multi-drug resistance. More than two-thirds of all women diagnosed with epithelial ovarian cancer will die from the disease (>15,000 deaths annually), a fact that has not changed in three decades. The standard treatment for patients with epithelial ovarian carcinoma (EOC) is initial debulking surgery followed by carboplatin-paclitaxel combination chemotherapy. Unfortunately, even with effective frontline chemotherapy, most patients with advanced EOC relapse and die as a result of resistant disease; five-year overall survival remains around 45% for all stages (27% for distant disease).

The studies in the Godwin group span over 25 years and have contributed to over 200 ovarian cancer-related publications and numerous clinical trials to help advance a field in desperate need of new treatments and better ways to detect cancer at an earlier stage. Their studies include establishing the first in vitro model of incessant ovulation, derived the first human ovarian surface epithelial cell cultures from BRCA1 and BRCA2 mutation carriers (in collaboration with Dr. Henry Lynch), cloning the human glutathione S-transferase gene (in collaboration with Alton Meister) and demonstrating the role of glutathione synthesis in resistance to cisplatin using human ovarian cancer cells that he derived (in collaboration with Drs. Thomas Hamilton & Robert Ozols) - these cell lines are used by countless researchers around the globe. He participated in the first study that identified AKT2 (in collaboration with Dr. Joseph Testa) and personally demonstrated its role in ovarian cancer oncogenesis.

Godwin was the first to study and establish a role for -synuclein in the pathogenesis of breast and ovarian cancer (and now many solid tumors). He reported the utility of monitoring circulating tumor cells in ovarian cancer clinical trials, and performed the first genomic siRNA screen to identify points of molecular vulnerability that are now being used in drug discovery efforts for novel therapies.

The Godwin research team's most recent studies at KUMC have 1) developed genetic signatures to predict likely response to ROS inducers, proteasome inhibitors and HSP90 inhibitors in ovarian cancer (Stephen Hyter, PhD), 2) uncovered an important role of TGF-/SMAD signaling and extracellular vesicles in platinum resistance (Jennifer Crow, PhD), 3) identified novel small molecule inhibitors of KIF15 activity that work in concert with KIF11 inhibition (Rebecca Wates, PhD in collaboration with Anuradha Roy, PhD, Frank Schoenen, PhD, Robert Hanzlik, PhD, and Philip Gao, PhD at KU Lawrence), 4) demonstrated that aurora A kinase regulates non-homologous end-joining and poly(ADP-ribose) polymerase function in ovarian cancer, 5) developed three-dimensional cell cultures of ovarian cancer cell lines and patient derived xenograft (PDX) models to screen new drugs that can reverse signatures of chemotherapy resistance (Jeff Hirst, PhD), and 6) developed the first integrated microfluidic chip for immunocapture and protein typing of circulating exosomes in ovarian cancer patient plasma samples to develop a test to improve the detection of this disease.

Translational Research and Biospecimens

Most people do not realize or appreciate the time, resources, and effort needed to establish highly annotated biobanks of human biospecimens and clinical data to support translational research. Dr. Godwin has been a leader in this field, and has established biobanks spanning multiple institutes and tens of thousands of participants. He and his team have contributed to NIH initiatives and have been listed as a source for the NCI Tissue Expediter since it beginnings. Godwin has been a tissue source site for both The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC I & III).

He established the Family Risk Assessment Program (FRAP) biosample repository at FCCC prior to the discovery of BRCA1 and BRCA2 to support the identification of inherited factors, which included >3,000 cancer-prone families. He also developed some of the earlier clinical tests (CLIA/CAP accredited) to screen women and men for mutations in BRCA1 and BRCA2. This resource contributed to the better understanding of the role of BRCA mutations in hereditary breast and ovarian cancer. His team was the first to show that loss of expression of BRCA1 via non-sense mediated decay and/or allele-specific expression was associated with breast cancer risk. Godwin served as a core member of the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), an international consortium that has assembled and is evaluating large cohorts (>30,000) of BRCA1 and BRCA2 mutation carriers for genetic modifiers of breast cancer risk.

Based on his past experiences, Godwin has developed a robust biospecimen repository (>20,000 participants) at KUMC and is working with Priyanka Sharma, MD to develop an invaluable Triple Negative Breast Cancer Registry. His group, primarily through the BDL (Director, Harsh Pathak, PhD) supports both investigator initiated and cooperative group trials of cancer to identify biomarkers predictive of response.

Molecular Therapeutics in Cancers

Dr. Godwin served as the Translational Science Co-chair and/or translational scientist for multiple Gynecologic Oncology Group (GOG) and Eastern Cooperative Oncology Group (ECOG) clinical trials evaluating molecularly targeted agents, such as AMG102, AMG386, AMG479, AMG706, cetuximab, dasatinib, everolimus, enzastaurin, gefitinib, lapatinib, RAD001, sorafenib, temsirolimus, and VEGF-TRAP and he is currently a member of the Early Therapeutics & Rare Cancers & Breast Committees for the Southwest Oncology Group (SWOG). In collaboration with scientists at, Godwin and his colleagues at Bristol Myers-Squibb were the first to demonstrate, in a Phase II clinical trial of advanced colon cancer, that patients with tumors expressing high gene levels of epiregulin and amphiregulin were more likely to have disease control on cetuximab treatment. Embedded in this study were important finding by his group indicating that the KRAS mutational status was highly informative of likely response to EGFR-targeted therapy.

Godwin's mutation study ultimately led to numerous other confirmatory studies and a Provisional Clinical Opinion statement by the American Society of Clinical Oncology that all patients with metastatic colorectal cancer who are candidates for anti-EFGR therapy (i.e., cetuximab and panitumumab) have their tumors tested for KRAS mutations. His clinical research efforts continue to explore and expand the use of molecular pathology in personalizing patient care and Godwin directs a CLIA/CAP accredited clinical molecular oncology laboratory (CMOL, Assistant Director, Ziyan Pessetto, PhD), which helps guide patient care on a daily basis.

The Pathogenesis of Gastrointestinal Stromal Tumor (GIST)

Dr. Godwin's interest in GIST began in the early 2000's. Using patient samples from the CSTI571-B2222 Phase II trial, his group was the first to report genetic markers that could predict the response of patients with metastatic/recurrent GIST to imatinib mesylate (also known as GleevecTM), an oral 2-phenylaminopyrimidine derivative that acts as a selective inhibitor against several receptor tyrosine kinases including KIT, PDGFRA, and BCR-ABL (selected as "The Best of MCT-10 Years" in November, 2011). His subsequent studies uncovered that imatinib has therapeutic benefit for GIST via KIT inhibition, but potentially independent of AKT activity and glucose deprivation. To expand the original profiling studies, Godwin's group directly assessed pre-treatment biopsy samples from a prospective neoadjuvant phase II trial (RTOG 0132) and identified an expanded 38-gene signature that included 18 KRAB-ZNF 91 subfamily members, 10 of which mapped to a single locus on chromosome 19p.

They were also the first to report a role of IGF-1R in the pathogenesis of GIST, especially in tumors that lacked kinase mutations. These so called "wild-type" tumors are clinically more resistant to imatinib-based therapies and have few gross genomic alterations. Godwin and other have now clearly shown that mutations in the SDH gene family inversely correlate with IGF-1R expression. Their studies led to the first clinical trials of wild-type pediatric and young adult GIST patients with an anti-IGF-1R targeted therapy. His studies at KUMC were the first to report a drug repurposing screen for GIST, which uncovered previously unappreciated therapies (e.g., auranofin (Ridaura®), an approved anti-arthritis agent) for the treatment of this disease (Ziyan Pessetto, PhD and Yan Ma, PhD).

Ewing Sarcoma

As part of a collaborative effort between investigators at Children's Mercy-Kansas City (CM) and KUMC, we have established a program to identify clinically informative biomarkers for Ewing Sarcoma (EWS) and to uncover new therapies for children with this disease. EWS is an aggressive bone and soft tissue cancer affecting children and young adults. Despite the significant advancements in treating localized EWS, the 5-year overall survival for patients with metastatic or relapsed/recurrent EWS is less than 20%. A possible contributor to this dismal statistic is that, aside from clinical symptomatology and radiographic imaging, no suitable biomarker exists which can specifically monitor disease progression or detect recurrence in EWS. To address this unmet need, Glenson Samuel, MD, FAAP (Assistant Professor, CM) is leading studies to identify predictive exosome-based biomarkers of recurrence and survival for children with EWS and to validate exosome miRNA signature(s) in clinical sample sets developed through the support of pediatric sarcoma patients and staff at Children's Mercy. Samuel has initiated the development of the first pediatric sarcoma biobank in the Kansas City region through the collaboration between CM and the Biospecimen Repository Core Facility (BRCF) at KUMC. Despite many years of attempts to intensify and improve chemotherapy regimens, survival of patients with EWS remains poor, especially for those who have progressive or metastatic disease at the time of diagnosis.

An important insight into the cause of EWS came from the discovery that these tumors harbor a chromosomal translocation between the EWSR1 (Ewing Sarcoma breakpoint region 1) gene on chromosome 22 and the FLI1 (Friend Leukemia virus Integration-1) gene on chromosome 11 (11;22)(q24;q12), which accounts for more than 85% of cases. The EWS-FLI1 fusion acts as an aberrant transcription factor that drives the malignant transformation and disease progression. However, therapeutics that directly target EWS-FLI1 gene have failed to demonstrate clinical benefits. Samuel and other members of the Godwin lab (Jennifer Crow, PhD and Rebecca Wates, PhD) have set out to develop alternative and novel treatments for Ewing Sarcoma and other progressive pediatric bone sarcomas by targeting and inhibiting proteins involved in mitotic spindle assembly.

Additionally, this group has focused to identify the downstream mediators of EWS-FLI1 and evaluate them as potential therapeutic options. Yan Ma, PhD, Ziyan Pessetto, PhD, and others are searching for new therapeutic approaches and molecular targets for Ewing Sarcoma through in silico prediction (in collaboration with Drs. Atul Butte and Bin Chen at UCSF) and in vitro drug screens. The goals of these collaborative studies are to identify new predictive biomarkers and therapies, which will benefit the children and young adults who are suffering from this rare but life-threatening disease.

Cellular Therapy

Studies lead by Neil Dunavin, MD (Assistant Professor, Division of Hematology and Cellular Therapeutics) and Meizhang Li, PhD, are focused on therapies in which cellular material is injected into a patient for therapeutic purposes. Significant progress has been made in the field of cellular therapy over the last decade; now, there are novel cellular therapeutics including modified T cells that are capable of targeting and killing cancer cells and pluripotent stem cells that are capable of regenerating diseased tissue. The focus of this work is on a subset of stem cells called "mesenchymal stem cells", or MSCs, and how to measure their activity when administered as a peripheral infusion for therapeutic purposes. MSCs are cells that reside in most tissues and function to maintain immune homeostasis in the human body. MSCs can be isolated, expanded in culture, and infused into the peripheral blood like a blood transfusion, where they have the capacity to suppress overactive immune responses by releasing several immunomodulatory signaling factors.

MSCs secrete thousands of different proteins, and dozens have been shown to be immunosuppressive, but it is not known which factor or which combination of factors is most responsible for the overall immunosuppressive effect. The extracellular vesicles released by MSCs have been shown to have potent immune suppressive properties. The goal of the cellular therapy group is to measure the kinetics of immune modulatory factors including extracellular vesicles in the blood of patients who receive peripheral infusion of MSCs in KUCC investigator-initiated clinical trial, and measure changes in the inflammatory environment and immune cell subsets. KUCC, through collaboration with the Midwest Stem Cell Therapy Center (MSCTC), has developed a novel MSC preparation (called MSCTC-0010) for use as a cellular therapy. In the phase 1 safety study MSCTC-0010 will be administered as an infusion to treat severe acute graft versus host disease (aGVHD), a syndrome of inflammation and tissue damage following allogeneic stem cell transplantation.

In the context of this clinical study Dunavin and colleagues will (1) characterize how inflammatory markers and established aGVHD biomarkers change over the course of therapy; (2) establish the time course of MSC-derived immunomodulatory factors including soluble proteins and extracellular vesicles; and (3) correlate these findings with aGVHD clinical outcomes. The knowledge gained from this study will help to inform the optimal dose, timing, and duration of MSC treatment, and has the potential to impact how MSCs are administered to treat a variety of inflammatory disorders.

Exosomes in Cancer

For the past several years the Godwin laboratory has been exploring the role of the exosomes in cancer initiation and progression and as biomarkers for early detection and response to therapy. They report the first evidence that GIST cells invade the interstitial stroma through the release of oncogenic KIT-containing exosomes, which triggers the phenotypic conversion of progenitor smooth muscle cells to tumor-promoting cells.

A study led by Safinur Atay, PhD, found that exosome release and subsequent MMP1 induction created a positive feedback-loop mechanism established between tumor and stromal cells which drives GIST development and offers new insights for potential therapeutic strategies to block GIST progression and metastatic spread. More generally, they sought to exploit exosomes as potential biomarkers to detect and monitor disease states (e.g., ovarian cancer, GIST, and Ewing Sarcoma). They therefore fabricated the first microfluidic platform (lab-on-a-chip) to streamline and expedite the exosome analysis pipeline by integrating specific immunoisolation and targeted protein analysis of circulating exosomes. Godwin's team is working with Drs. Steven Soper and Yong Zeng at KU to develop and test additional microfluidic platforms to capture circulating biomarkers, CTCs and exosomes. In collaboration with Nikki Nollen, PhD (KUMC), they are interrogating circulating exosomes and their molecular content in Black and White smokers as novel biomarkers to assess how they relate to race, cigarette consumption, nicotine exposure, and cancer risk.

Godwin's research group has also established the proteome of some tumor-derived exosomes (e.g., ovarian cancer, GIST, and EWS led by Atay and Samuel) and are exploiting the exosomal cargo to develop to develop liquid-based biopsies to diagnosis and monitoring disease. They foresee that the novel microfluidic devices will form the basis for critically needed clinical tools for advancing the biology and clinical utilization of CTCs, cfDNA, and exosomes in the diagnosis and monitoring of disease during therapy.

The Godwin research program is both diverse and dynamic in regards to addressing unmet needs for individuals with cancer.

Last modified: Aug 18, 2017
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Susan Ard
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Clinical Molecular Oncology
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