Skip to Content
Translational Research Program (TRP)
Last Updated: 01/24/17

SPORE Advances

[+] Bladder

Colin P.N. Dinney M.D. and David J. McConkey Ph.D. — The University of Texas MD Anderson SPORE in Genitourinary Cancer

Project 1: Improving Diagnosis of Bladder Cancer

Project Co-leaders: Bogdan Czerniak, Ph.D. and H. Barton Grossman, M.D.

Meta-Analysis of the Luminal and Basal Subtypes of Bladder Cancer and the Identification of Signature Immunohistochemically Markers for Clinical Use

This study validated the luminal and basal subtypes of bladder cancer in a set of clinical trials and identified signature biomarkers that may facilitate disease classification in the clinical laboratory setting. Luminal tumors showed upregulation of PPAR gamma genes and overexpression of E-Cadherin, HER2/3, Rab-25, and Src, as well as an enrichment of a specific set of mutations. Basal Tumors had an expression signature similar to the basal layer of the normal urothelium. Basal Tumors showed upregulation of p63 genes, an enrichment for TP53 and RB1 mutations, as well as overexpression of CD49, Cyclin B1, and EGFR. Basal bladder cancers were more aggressive. These biomarker patterns have application for prognosis and therapeutic stratification.

Publication:
Dadhania V, Zhang M, Zhang L, Bondaruk J, Majewski T, Siefker-Radtke A, Guo CC, Dinney C, Cogdell DE, Zhang S, Lee S, Lee JG, Weinstein JN, Baggerly K, McConkey D, Czerniak B. Meta-Analysis of the Luminal and Basal Subtypes of Bladder Cancer and the Identification of Signature Immunohistochemical Markers for Clinical Use. EBioMedicine. 2016 Oct;12:105-117.

Project 2: Role of MicroRNA in Bladder Cancer Risk and Outcome: Genome-wide Analysis

Project Co-Leaders: Xifeng Wu, M.D., Ph.D.; Ashish Kamat, M.D.; and Seth Lerner, M.D.

Gene Expression Profile of the Clinically Aggressive Miropapillary Variant of Bladder Cancer

Micropapillary carcinoma manifests aggressive clinical behavior with a high propensity for metastasis. In this study 43 patient tumors were retrospectively characterized with whole-genome expression profiling. Results showed that micropapillary cancer is almost exclusively luminal. This study also showed that a striking feature of micropapillary cancer was downregulation of microRNA miR-296, and activation of chromatin-remodeling complex RUVBL1. These observations have important implications for prognosis and therapy development for micropapillary bladder cancer.

Publication:
Guo CC, Dadhania V, Zhang L, Majewski T, Bondaruk J, Sykulski M, Wronowska W, Gambin A, Wang Y, Zhang S, Fuentes-Mattei E, Kamat AM, Dinney C, Siefker-Radtke A, Choi W, Baggerly KA, McConkey D, Weinstein JN, Czerniak B. Gene Expression Profile of the Clinically Aggressive Micropapillary Variant of Bladder Cancer. Eur Urol. 2016 Mar 15.

[+] Brain

Mitchel S. Berger, M.D. — University of California, San Francisco Brain Tumor SPORE

Project 3: Novel Approaches for Improving Pediatric BRAFV600E Glioma Patient Outcomes

Project Co-leaders: C. David James, Ph.D., Theodore Nicolaides, M.D., and Michael Prados, M.D.

Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma

Radiation therapy increased effectiveness of an inhibitor of BRAF V600E (PLX4720- FDA-approved vemurafenib) in glioma cells in vitro and in an intracranial xenograft mouse model of BRAF V600E-mutated gliomas. In these preclinical studies of high grade glioma with mutated BRAF V600E mutation, the combination showed a survival advantage in vivo with tissue analysis showing reduction of cells in S phase, decreased KI67, and cell proliferation, and increased cleaved caspase 3, and increased γH2AX and p21 compared to control mice. These studies are part of an ongoing effort to optimize treatment of pediatric brain tumors with the BRAF V600E mutation.

Publication:
Dasgupta T, Olow AK, Yang X, Hashizume R, Nicolaides TP, Tom M, Aoki Y, Berger MS, Weiss WA, Stalpers LJ, Prados M, James CD, Mueller S, Haas-Kogan DA. Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma. J Neurooncol. 2016 Feb;126(3):385-93. doi: 10.1007/s11060-015-1939-2. Erratum in: J Neurooncol. 2016 Feb;126(3):395.

Frederick F. Lang, M.D. — University of Texas/M.D. Anderson Cancer Center SPORE in Brain Cancer

miR-182-5p Induced by STAT3 Activation Promotes Glioma Tumorigenesis

In malignant glioma the oncogenic transcription factor STAT3, plays a critical role in many processes including cancer growth, invasion and metastasis. In preclinical studies, STAT3 was found to be linked to miR-182-5p which comes from a class of small, noncoding RNA molecules that are involved in posttranscriptional regulation of gene expression. A downstream target of miR-182-5p is a tumor suppressor gene called protocadherin-8 (PCDH8). This study reports that STAT3 activation upregulates expression of miR-182-5p which then represses PCDH8 expression, leading to increased glioma cell growth, migration, and invasion. Human glioma tissue samples confirmed that the expression of PCDH8 in the tumors was significantly lower while the level of p-STAT3 in tumors was higher than that in adjacent normal brain tissues. Targeting the STAT3/miR-182-5p/PCDH8 axis may increase therapies for human glioma.

Publication:
Xue J, Zhou A, Wu Y, Morris SA, Lin K, Amin S, Verhaak R, Fuller G, Xie K, Heimberger AB, Huang S. miR-182-5p Induced by STAT3 Activation Promotes Glioma Tumorigenesis. Cancer Res. 2016 Jul 15;76(14):4293-304. doi: 10.1158/0008-5472.CAN-15-3073.

[+] Breast

C. Kent Osborne — Baylor College of Medicine Translational Research SPORE in Breast Cancer

Project 3: Intermittent Ruxolitinib to Target STAT5 Activation for Breast Cancer Prevention

Project Co-leaders: Yi Li, Ph.D. and C. Kent Osborne, M.D.

The role of STAT3 and STAT5 in human breast atypical ductal hyperplasia progression

Signal Transducer and Activation of Transcription factors (STAT3 and STAT5) play important roles in breast epithelial cell differentiation, proliferation, and apoptosis. A complementary expression pattern of pSTAT3 and pSTAT5 in ADH suggests that these two transcription factors may have feedback inhibitory effects on each other during early stages of breast cancer evolution, and that disruption of this inverse relationship may be important in the progression from early lesions to cancer, which exhibits positive association between pSTAT3 and pSTAT5.

Publication:
Shi A, Dong J, Hilsenbeck S, Bi L, Zhang H, Li Y. The Status of STAT3 and STAT5 in Human Breast Atypical Ductal Hyperplasia. PLoS One. 2015;10(7):e0132214.

Eric Winer — Dana-Farber/Harvard SPORE in Breast Cancer

Project 4: Combinatorial Approaches to Prevent Early Adaptive Responses

Project Co-leaders: Joan Brugge Ph.D. and Jose Baselga, M.D., Ph.D

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease with limited options for targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here the investigators report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, TNBC resistance was associated with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A that was identified here as a principal BRD4 serine phosphatase. These studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.

Publication:
Shu S, Lin CY, He HH, Witwicki RM, Tabassum DP, Roberts JM, Janiszewska M, Huh SJ, Liang Y, Ryan J, Doherty E, Mohammed H, Guo H, Stover DG, Ekram MB, Peluffo G, Brown J, D'Santos C, Krop IE, Dillon D, McKeown M, Ott C, Qi J, Ni M, Rao PK, Duarte M, Wu SY, Chiang CM, Anders L, Young RA, Winer EP, Letai A, Barry WT, Carroll JS, Long HW, Brown M, Liu XS, Meyer CA, Bradner JE, Polyak K. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature. 2016 Jan 21;529(7586):413-7. doi: 10.1038/nature16508.

[+] Endometrial

Karen Lu, M.D. — University of Texas/M.D. Anderson Cancer Center Endometrial Cancer SPORE

Project 1: Novel Targeted Strategies for Prevention and Conservative Management of Complex Atypical Hyperplasia and Grade 1 Endometrioid

Project Co-leaders: Karen H. Lu, M.D.; Samuel C. Mok, Ph.D.; Melinda S. Yates, Ph.D.; and Shannon N. Westin, M.D.

Developing differential approaches for treatment of obese and non-obese endometrial cancer patients

Endometrial cancer incidence is increasing, due in part to a strong association with obesity. Molecular alterations associated with endometrial carcinogenesis must be interpreted in the context of body mass index. Investigators have shown that PTEN loss was associated with improved progression-free survival only in obese (BMI≥30) patients. Molecular changes related to KRAS activation and inflammation are significantly more common in obese patients with complex atypical hyperplasia.

Publications:
Westin SN, Ju Z, Broaddus RR, Krakstad C, Li J, Pal N, Lu KH, Coleman RL, Hennessy BT, Klempner SJ, Werner HM, Salvesen HB, Cantley LC, Mills GB, Myers AP. PTEN loss is a context-dependent outcome determinant in obese and non-obese endometrioid endometrial cancer patients. Mol Oncol. 2015 Oct;9(8):1694-703.

Berg A, Hoivik EA, Mjøs S, Holst F, Werner HM, Tangen IL, Taylor-Weiner A, Gibson WJ, Kusonmano K, Wik E, Trovik J, Halle MK, Oyan AM, Kalland KH, Cherniack AD, Beroukhim R, Stefansson I, Mills GB, Krakstad C, Salvesen HB. Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients. Oncotarget. 2015 Jan 20;6(2):1327-39.

[+] Gastrointestinal

Adam Bass, M.D. and Nabeel M. Bardeesy, Ph.D. — DF/HCC SPORE in Gastrointestinal Cancer

Project 4: Overcoming Resistance to RAF Inhibition in BRAF-mutant Colorectal Cancer

Project Co-Leaders: Levi Garraway, M.D., Ph.D. and Ryan B. Corcoran, M.D., Ph.D.

Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAFV600-mutant colorectal cancer

BRAF-V600 missense mutations (usually V600E) are present in a subset of colorectal cancers and results in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway.  Inhibition of BRAF with dabrafenib or downstream component MEK with trametinib has been effective in BRAF-V600 melanoma; however, as monotherapies these agents have been much less effective in BRAF-V600 colorectal cancer.  In this study the investigators evaluated the combination of dabrafenib and trametinib in 43 patients with BRAF-V600 mutant colorectal cancer.  Five patients (12%) achieved a partial response or better, including one complete response. This study is an important first step in exploring the vulnerability of BRAF-mutant colorectal cancer to targeted therapies.

Publication:
Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, Hamid O, Messersmith WA, Daud A, Kurzrock R, Pierobon M, Sun P, Cunningham E, Little S, Orford K, Motwani M, Bai Y, Patel K, Venook AP, Kopetz S.  Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer.  J. Clin. Oncol. 2015 Dec 1;33(34):4023-31.

Sanford D. Markowitz, M.D., Ph.D. — Case Western Reserve University Gastrointestinal SPORE

Developmental Research Program

Co-Directors: Nathan A. Berger, M.D.; Sanford Markowitz, M.D., Ph.D.; and Neal J. Meropol, M.D.

DNMT1-associated long non-coding RNAs regulate global gene expression and DNA methylation in colon cancer

Genetics researchers from Case Western Reserve School of Medicine have identified a novel long non-coding RNA (lncRNA), dubbed DACOR1 (for DNMT1-Associated Colon Cancer Repressed lncRNA-1), that has the potential to stymy the growth of tumor cells in the second most-deadly form of cancer in the U.S. — colorectal cancer. The researchers found that this lncRNA is present in cells of healthy colons, but becomes suppressed in those carrying the disease. More important, this lncRNA interacts with a key enzyme known as DNMT1 that has essential functions in all healthy cells of the body.

Publication:
Merry CR, Forrest ME, Sabers JN, Beard L, Gao XH, Hatzoglou M, Jackson MW, Wang Z, Markowitz SD, Khalil AM. DNMT1-associated long non-coding RNAs regulate global gene expression and DNA methylation in colon cancer. Hum Mol Genet. 2015 Nov 1;24(21):6240-53.

[+] Head & Neck

David Sidransky, M.D. — Johns Hopkins University Head & Neck SPORE

Project 2: HNSCC — From Cancer Genomics to Personalized Biomarkers

Project Co-leaders: David Sidransky, M.D. and Nishant Agrawal, M.D.

Proof of principle study identified tumor DNA shed into the saliva and blood of 93 head and neck cancer patients

In this study of 93 head and neck cancer patients, tumor DNA was detected in the saliva of 76% of patient samples and in the blood of 87% of patient samples. In patients who gave both blood and saliva samples, 96% of the patients had tumor DNA detected in at least one of the body fluids. Moreover, saliva tests were more efficient than blood tests in detecting oral cavity cancers, and conversely, blood tests were more efficient than saliva tests in detecting cancers in the larynx, hypopharynx and oropharynx. The investigators found that saliva tests correctly identified 100% of the oral cavity cancers, compared with 47% oropharynx cancers, 70% larynx cancers, and 67% of hypopharynx cancers.  And blood tests correctly identified 91% of oropharynx cancers, 86% of larynx cancers, and 100% of hypopharynx cancers. 

Publication:
Wang Y, Springer S, Mulvey CL, Silliman N, Schaefer J, Sausen M, James N, Rettig EM, Guo T, Pickering CR, Bishop JA, Chung CH, Califano JA, Eisele DW, Fakhry C, Gourin CG, Ha PK, Kang H, Kiess A, Koch WM, Myers JN, Quon H, Richmon JD, Sidransky D, Tufano RP, Westra WH, Bettegowda C, Diaz LA Jr, Papadopoulos N, Kinzler KW, Vogelstein B, Agrawal N. Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. Sci Transl Med. 2015 Jun 24;7(293):293ra104.

News Articles and Press Releases:
Reinberg, S. (2015, July 1). Saliva, blood tests to detect cancer are still in early stages. Chicago Tribune. Retrieved from http://www.chicagotribune.com/lifestyles/health/sc-hlth-0701-blood-saliva-cancer-tests-20150701-story.html.

Science Daily. (2015). DNA shed from head and neck tumors detected in blood, saliva [Press Release]. Retrieved from https://www.sciencedaily.com/releases/2015/06/150624143201.htm.

[+] Hyperactive RAS

D. Wade Clapp, M.D. and Kevin M. Shannon, M.D. — Indiana University/UCSF Developmental and Hyperactive Ras Tumor (DHART) SPORE

Project 1: Molecular and Genetic Features across Mouse and Human Plexiform Neurofibromas to Inform Clinical Trials

Project Co-leaders: D. Wade Clapp, M.D.; Jaishri Blakeley, M.D.; Brigitte Widemann, M.D.; and Lu Le, MD, Ph.D.

Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas

Plexiform neurofibromas (pNF) are pathognomonic nerve and soft tissue tumors of neurofibromatosis type I (NF1), which are highly resistant to conventional chemotherapy and associated with significant morbidity/mortality. Sunitinib malate is a potent, highly selective RTK inhibitor with activity against c-Kit, PDGFR, and VEGFR, which have been implicated in the pathogenesis of these lesions. The investigators evaluated the efficacy of sunitinib malate in a preclinical Krox20;Nf1flox/- pNF murine model. The results demonstrated the efficacy of sunitinib in reducing tumor burden in Krox20;Nf1flox/- mice. These preclinical findings demonstrate the utility of inhibiting multiple RTKs in pNF and provide insights into the design of future clinical trials.

Publication:
Shu S, Lin CY, He HH, Witwicki RM, Tabassum DP, Roberts JM, Janiszewska M, Huh SJ, Liang Y, Ryan J, Doherty E, Mohammed H, Guo H, Stover DG, Ekram MB, Peluffo G, Brown J, D'Santos C, Krop IE, Dillon D, McKeown M, Ott C, Qi J, Ni M, Rao PK, Duarte M, Wu SY, Chiang CM, Anders L, Young RA, Winer EP, Letai A, Barry WT, Carroll JS, Long HW, Brown M, Liu XS, Meyer CA, Bradner JE, Polyak K. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature. 2016 Jan 21;529(7586):413-7.

[+] Kidney

David F. McDermott, M.D. and William G. Kaelin, Jr., M.D. — DF/HCC Kidney Cancer SPORE

CORE 2: DF/HCC Kidney Cancer SPORE Tissue, Acquisition, Pathology and Clinical Data

Core Co-Leaders: Sabina Signoretti, M.D.; Toni Choueiri, M.D.; and Rupal Bhatt, M.D

Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma

This multinational study classified renal cell carcinoma of various histologic types into nine major genomic subtypes, based on a multi-dimensional and comprehensive molecular characterization of 894 renal cell carcinomas. The site of origin within the kidney nephron was among the key determinants in the classification. Subtype associated with aggressive clear cell renal cell carcinoma were associated with the highest levels of immune checkpoint marker and molecular signatures of T cell infiltrates. The results offer promise for the development of therapeutic strategies tailored for each RCC disease subset.

Publication:
Chen F, Zhang Y, Şenbabaoǧlu Y, Ciriello G, Yang L, Reznik E, Shuch B, Micevic G, De Velasco G, Shinbrot E, Noble MS, Lu Y, Covington KR, Xi L, Drummond JA, Muzny D, Kang H, Lee J, Tamboli P, Reuter V, Shelley CS, Kaipparettu BA, Bottaro DP, Godwin AK, Gibbs RA, Getz G, Kucherlapati R, Park PJ, Sander C, Henske EP, Zhou JH, Kwiatkowski DJ, Ho TH, Choueiri TK, Hsieh JJ, Akbani R, Mills GB, Hakimi AA, Wheeler DA, Creighton CJ. Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma. Cell Rep. 2016 Mar 15;14(10):2476-89.

[+] Leukemia

Daniel C. Link, M.D. — Washington University SPORE in Leukemia

Project 4: Epigenetic Modulation of Graft Versus Host Disease and Graft Versus Leukemia

Project Co-leaders: John F. DiPersio, M.D., Ph.D. and Peter Westervelt, M.D., Ph.D.

A new approach to improve effectiveness of stem cell transplantation to treat acute myeloid leukemia (AML)

Allogeneic stem cell transplantation is often used to treat AML, but relapses are common. In the case of a relapse, salvage chemotherapy followed by donor lymphocyte infusion (DLI) without prophylactic immunosuppression is often used. However, many patients develop severe graft-vs-host disease after this procedure. Investigators from the Washington University leukemia SPORE have found in mice models that azacitidine administered after the the DLI alleviates graft-vs-host disease while preserving the graft-vs-leukemia effect. In this study they go on to demonstrate, via a phase I clinical trial, that azacitidine administered to AML patients post-DLI is well tolerated and holds promise to prevent graft-vs-host disease after DLI.

Publication:
Ghobadi A, Choi J, Fiala MA, Fletcher T, Liu J, Eissenberg LG, Abboud C, Cashen A, Vij R, Schroeder MA, Pusic I, Stockerl-Goldstein K, Jacoby M, Uy G, DiPersio J, Westervelt P. Phase I study of azacitidine following donor lymphocyte infusion for relapsed acute myeloid leukemia post allogeneic stem cell transplantation. Leuk Res. 2016 Oct; 49:1-6.

[+] Lung

Eric B. Haura, M.D. — H. Lee Moffitt Cancer Center SPORE in Lung Cancer

Project 1: SEMA3F and ZEB1 in Lung Cancer: Therapy & Target Gene Discovery

Project Co-leaders: Harry A. Drabkin, M.D.; Robert M. Gemmill, Ph.D.; and Daniel C. Chan, Ph.D.

Epigenetic therapy potentiates immune responses and immunotherapy interventions in lung cancer

The Moffitt Cancer Center Lung Cancer SPOREs leads the way in the characterization of interactions between epigenetic interventions and the immune system in lung cancer patients. Moffitt Cancer Center researchers have identified a class of drugs (histone deacetylase inhibitors) that improve the activity of immunotherapeutic antibodies by stimulating the movement of T cells into a tumor and enhancing their effector activity. These observations suggest that HDAC inhibitors, including romidepsin, could work in conjunction with other immune-stimulating agents to enhance an immune response against tumors. The researchers confirmed this by showing in pre-clinical studies that romidepsin combined with an antibody that targets PD-1 results in greater anti-tumor activity than either agent alone and increases the levels and activity of T cells within the tumor. A clinical trial testing the combination is under way.

Publication:
Zheng H, Zhao W, Yan C, Watson CC, Massengill M, Xie M, Massengill C, Noyes DR, Martinez GV, Afzal R, Chen Z, Ren X, Antonia SJ, Haura EB, Ruffell B, Beg AA. HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma. Clin Cancer Res. 2016 Aug 15;22(16):4119-32. doi: 10.1158/1078-0432.CCR-15-2584.

Press Release:
American Association for the Advancement of Science. (2016). Histone deacetylase inhibitors enhance immunotherapy in lung cancer models, say Moffitt researchers [Press release].

Paul Bunn, Jr., M.D. — University of Colorado Cancer Center Lung SPORE

Project 2: Growth Factor Inhibitors for Lung Cancer Therapy and Prevention

Project Co-leaders: Paul A. Bunn, Jr., M.D. and Daniel C. Chan, Ph.D.

Waxing and waning of MET amplification in EGFR mutated NSCLC in response to presence and absence of erlotinib selection pressure

Somatic sensitizing mutations in the epidermal growth factor receptor (EGFR) are associated with response to EGFR tyrosine kinase inhibitors (TKIs), however acquired resistance and subsequent progression of disease inevitably occurs. One such mechanism of acquired resistance (AR), a second site mutation in the EGFR, T790M, has been shown to wax and wane in the presence and absence of selection pressure in the form of EGFR TKI therapy. Another less common mechanism of AR is development of a secondary driver pathway via MET amplification. The project describes waxing and waning MET amplification in to the presence and absence of erlotinib supporting the idea that mechanisms of AR other than T790M also respond to EGFR TKI selection pressure, with implications for standard practice and clinical trial design.

Publication:
Womack JP, Varella-Garcia M, Camidge DR. Waxing and Waning of MET Amplification in EGFR-Mutated NSCLC in Response to the Presence and Absence of Erlotinib Selection Pressure. J Thorac Oncol. 2015 Dec;10(12):e115-8.

[+] Lymphoma

Helen Heslop M.D. and Malcolm Brenner, M.D., Ph.D. — SPORE in Lymphoma

Project 2: Chimeric T — Cell Antigens Targeting Ig Kappa Light Chain in B-Cell Lymphoma

Project Co-leaders: Gianpietro Dotti, M.D. and Carlos Ramos, M.D.

A Method to Target Malignant B cells that has Reduced Toxicity

Within recent years, methods have been developed that involve engineering the patient's own T cells with chimeric antigen receptors (CARs) to target malignant B cells via their CD19 marker. However, this approach depletes normal B cells (which also express CD19) and causes severe hypogammaglobulinemia. B cells express immunoglobulin light chains either of the kappa subtype or lambda subtype and, similarly, monoclonal malignant B cells have one or the other of these light chain subtypes. The goal of this study is to specifically target the light chain subtype that is carried on the malignant B cells so that the normal B cells with the other subtype are spared. These investigators have engineered CAR T cells to recognize kappa light chains and have shown in this study that infusion of these cells into lymphoma and myeloma patients who have kappa-positive B cell malignancies is feasible, safe, and can lead to complete clinical responses.

Publication:
Ramos CA, Savoldo B, Torrano V, Ballard B, Zhang H, Dakhova O, Liu E, Carrum G, Kamble RT, Gee AP, Mei Z, Wu MF, Liu H, Grilley B, Rooney CM, Brenner MK, Heslop HE, Dotti G. Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J Clin Invest. 2016 Jul 1;126(7):2588-96.

[+] Ovarian

Scott H. Kaufmann, M.D., Ph.D, and Lynn C. Hartmann, M.D. — Mayo Clinic SPORE in Ovarian Cancer

Project 3: Metformin as a Metabolic Therapeutic in Ovarian Cancer

Project Co-leaders: Ernst Lengyel, M.D., Ph.D.; Iris Romero, M.D.; Gini Fleming, M.D.; and S. Diane Yamada, M.D.

Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models

In the prevention mouse model, mice that were pretreated with metformin prior to IP injection of an ovarian cell line had 60% fewer tumor implants compared with controls. In the treatment study, mice that were treated with paclitaxel plus metformin prior to tumor injection had a 60% reduction in tumor weight compared with controls demonstrating cumulative effect of paclitaxel/metformin combination. Stronger responses were induced in normoglycemic mice as compared to hyperglycemic.

Publications:
Litchfield LM, Mukherjee A, Eckert MA, Johnson A, Mills KA, Pan S, Shridhar V, Lengyel E, Romero IL. Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer. Oncotarget. 2015 Sep 15;6(27):23548-60.

Lengyel E, Litchfield LM, Mitra AK, Nieman KM, Mukherjee A, Zhang Y, Johnson A, Bradaric M, Lee W, Romero IL. Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models. Am J Obstet Gynecol. 2015 Apr;212(4):479.e1-479.e10.

Kunle O. Odunsi M.D., PhD., Kirsten Moysich, Ph.D., and Robert Edwards, M.D. — Roswell Park Cancer Institute/ University of Pittsburgh Ovarian Cancer SPORE

Project 3: MHC-Restricted and MHC-Non-Restricted Targeting of Ovarian Cancer by αDC1-induced CTLs

Project Co-leaders: Robert Edwards, M.D. and Pawel Kalinski, M.D., Ph.D.

HLA superfamily assignment is a predictor of immune response to cancer testis antigens and survival in ovarian cancer

The investigators characterized the association between major histocompatibility complex (MHC) types and spontaneous antibody development to the cancer testis (CT) antigen NY-ESO-1. Out of 126 patients identified, 81% were expression positive and 48% had spontaneous antibody responses to NY-ESO-1. There was an association between HLA-B superfamily and seropositivity among patients with tumors expressing NY-ESO-1 (p<0.001). The differences in HLA-B superfamily assignment were driven by HLA-B44. Among all patients, the B27 superfamily was over-represented compared with the general population (p<0.001).

Publication:
Szender JB, Eng KH, Matsuzaki J, Miliotto A, Gnjatic S, Tsuji T, Odunsi K. HLA superfamily assignment is a predictor of immune response to cancer testis antigens and survival in ovarian cancer. Gynecol Oncol. 2016 Jul;142(1):158-62. doi: 10.1016/j.ygyno.2016.04.017.

[+] Pancreatic

Alison P. Klein, M.H.S., Ph.D. — Johns Hopkins University SPORE in Gastrointestinal Cancers

Project 2: Markers for Screening and Prognosis

Project Co-leaders: Michael Goggins, M.D. and Kenneth Kinzler, M.D.

Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer

Investigators have shown that annexin A2 helps usher a protein called Semaphorin 3D (Sema3D) out of pancreatic cancer cells. Once outside the cells, Sema3D joins with another molecule to fuel the cancer’s spread. Sema3D is a protein that guides the projecting arms of nerve cells, axons, as the nerve cells grow and develop. Thus, AnxA2 and Sema3D may be new therapeutic targets and prognostic markers of metastatic PDA.

Publication:
Foley K, Rucki AA, Xiao Q, Zhou D, Leubner A, Mo G, Kleponis J, Wu AA, Sharma R, Jiang Q, Anders RA, Iacobuzio-Donahue CA, Hajjar KA, Maitra A, Jaffee EM, Zheng L. Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer. Sci Signal. 2015 Aug 4;8(388):ra77.

[+] Prostate

Inter-SPORE Collaboration: Peter S. Nelson, M.D. — Pacific Northwest Prostate Cancer SPORE and Howard Scher, M.D.-Memorial Sloan Kettering Cancer Center

SPORE Collaborators: Peter S. Nelson, M.D.; Howard Scher, M.D.; Arul Chinnayan, M.D., Ph.D.; Wassim Abida, M.D.; Bruce Montgomery, M.D.; Ph.D.; Charles Sawyers, M.D.; and Philip Kantoff, M.D.

Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer

This multicenter study reported that the incidence of germline mutations in genes that mediated the process of DNA-repair in men with metastatic prostate cancer was 11.8%, and that this germline mutation frequency was markedly higher than that found among men with localized prostate cancer. Age of diagnosis and family history were not associated with the frequency of the germline mutations of the DNA-repair genes studied.

Publication:
Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, Garofalo A, Gulati R, Carreira S, Eeles R, Elemento O, Rubin MA, Robinson D, Lonigro R, Hussain M, Chinnaiyan A, Vinson J, Filipenko J, Garraway L, Taplin ME, AlDubayan S, Han GC, Beightol M, Morrissey C, Nghiem B, Cheng HH, Montgomery B, Walsh T, Casadei S, Berger M, Zhang L, Zehir A, Vijai J, Scher HI, Sawyers C, Schultz N, Kantoff PW, Solit D, Robson M, Van Allen EM, Offit K, de Bono J, Nelson PS. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53.

Peter S. Nelson, M.D. — Pacific Northwest Prostate Cancer SPORE

Core B: Tissue & Specimen

Core Co-Directors: Robert Vessella, Ph.D. and Lawrence True, M.D.

Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer

This study analyzed multiple tumors from men with disseminated prostate cancer by exome sequencing, array comparative genomic hybridization and RNA transcript profiling, and compared the diversity among metastases with an individual. They found that the overall mutation burden, copy number alteration burden, androgen receptor activity signature and cell cycle output were highly concordant across tumors within an individual. The data indicate that, while there are exceptions, the evaluation of a single metastasis provides a good assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual and therefore, may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.

Publications:
Kumar A, Coleman I, Morrissey C, Zhang X, True LD, Gulati R, Etzioni R, Bolouri H, Montgomery B, White T, Lucas JM, Brown LG, Dumpit RF, DeSarkar N, Higano C, Yu EY, Coleman R, Schultz N, Fang M, Lange PH, Shendure J, Vessella RL, Nelson PS. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med. 2016 Apr;22(4):369-78.

[+] Sarcoma

Samuel Singer, M.D. — Memorial Sloan-Kettering Cancer Center SPORE in Soft Tissue Sarcoma

Project 2: Developing New Strategies for Targeting PDGFR/P13K/AKT Pathways in Sarcoma

Project Co-Leaders: Gary K. Schwartz, M.D. and William Tap, M.D.

FDA approves the combination of Olaratumab and doxorubicin for treatment of soft tissue sarcomas

The MSKCC Sarcoma SPORE is cited as a sole scientific grant besides the cancer center grant in the seminal publication of the Phase 1-2 clinical trial that led the FDA breakthrough approval of this anti-PDGFR-alpha antibody in combination with doxorubicin. This study is directly related to SPORE project 2.

Publications:
Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, Agulnik M, Cooney MM, Livingston MB, Pennock G, Hameed MR, Shah GD, Qin A, Shahir A, Cronier DM, Ilaria R Jr, Conti I, Cosaert J, Schwartz GK. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016 Jul 30;388(10043):488-97. doi: 10.1016/S0140-6736(16)30587-6. Erratum in: Lancet. 2016 Jul 30;388(10043):464.

[+] Skin

Ruth Halaban, Ph.D. — Yale University SPORE in Skin Cancer

Project 1: Genomic Sunlight Dosimeters for Melanoma Prevention

Project Co-Leaders: Douglas Brash, Ph.D.; Deepak Narayan, M.D.; and Michael Krauthammer, Ph.D.

RASopathy gene mutations in melanoma and exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas

Using next-generation sequencing of melanomas, large numbers of genetic changes are found including frequent activating driver mutations in BRAF, and NRAS, along with inactivating mutations in the tumor suppressor genes CDKN2A and TP53. The work of the Yale SPORE has identified the third most frequently mutated gene in melanoma to be NF1 (which negatively regulates RAS), a key tumor suppressor lost in melanomas . NF1 requires additional concurrent mutations from the MAPK pathway to promote melanomagenesis. NF1 links melanoma to certain disorders, called “RASopathies” such as neurofibromatosis and Noonan and Legius syndromes, where germline mutations are found in the RAS/MAPK signaling pathway genes.

Publications:
Halaban R, Krauthammer M. RASopathy Gene Mutations in Melanoma. J Invest Dermatol. 2016 Sep;136(9):1755-9.

Krauthammer M, Kong Y, Bacchiocchi A, Evans P, Pornputtapong N, Wu C, McCusker JP, Ma S, Cheng E, Straub R, Serin M, Bosenberg M, Ariyan S, Narayan D, Sznol M, Kluger HM, Mane S, Schlessinger J, Lifton RP, Halaban R. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet. 2015 Sep;47(9):996-1002.