Eric Nakakura, M.D., Ph.D.

Research Overview

Neuroendocrine tumors (NETs) of the small intestine and pancreas frequently spread throughout the body (i.e., metastasize). Surgery is often not possible for patients with advanced disease, and current therapies are ineffective for shrinking tumors and durable palliation of debilitating symptoms, often caused by the release of hormones into the blood. Dr. Nakakura and his colleagues' long-term goal is to find the causes of NETs of the small intestine and pancreas, which can lead to earlier diagnosis and ultimately a cure.

How And Why Neuroendocrine Tumors Develop

In collaboration with Matthew Meyerson (Broad Institute, Dana-Farber Cancer Institute) and Chrissie Thirwell ( University College London Cancer Institute), Dr. Nakakura is studying the causes of small intestine neuroendocrine tumors utilizing state-of-the art genetic and epigenetic technologies of primary tumors and single cell analyses of precursor lesions. 

Funding: Neuroendocrine Tumor Research Foundation (NETRF) Accelerator Grant

Novel Neuroendocrine Tumor Models

A particular interest and focus of Dr. Nakakura's translational research is the development of novel neuroendocrine tumor models.  His laboratory successfully developed a patient-derived pancreatic neuroendocrine tumor (PNETs) xenograft model--the onlysuch model in the world--that faithfully retains the pathologic and genetic aberrations typical of human PNETs.  Dr. Nakakura's laboratory is collaborating with investigators worldwide, studying mechanisms of resistance to current therapies, novel small molecule targeted therapies, CAR T cell therapy, peptide receptor radionucleotide therapy, and the unfolded protein response. 

Funding: Neuroendocrine Tumor Research Foundation (NETRF), American Association for Cancer Research (AACR) 

Identification of Regulators of NET growth and Hormone Production

Dr. Nakakura's laboratory has a long-term interest to elucidate the transcriptional and signaling events critical to the pathogenesis of NETs of the small intestine and pancreas, which can identify novel targets for diagnosis and treatment. His approach has been to turn to developmental biology for clues.  Dr. Nakakura and collegues have found that the same transcription factors (Ascl1, Nkx2.2, Fev, Scratch)^1-4 and signaling pathways (Notch)² that function in the normal development of endocrine cells throughout the body also act to regulate NET hormone production and growth, as well as metastasis.  These findings that conserved pathways of neuroendocrine differentiation function in cancer have also shed important insight into normal gut endocrine cell development. 

¹ Nakakura EK, Watkins DN, Schuebel KE, Sriuranpong V, Borges MW, Nelkin BD, Ball DW. Mammalian Scratch: a neural-specific Snail family transcriptional repressor. Proc Natl Acad Sci U S A, Mar/27/2001;98(7):4010-5. PMID: 11274425 

²  Nakakura EK, Sriuranpong VR, Kunnimalaiyaan M, Hsiao EC, Schuebel KE, Borges MW, Jin N, Collins BJ, Nelkin BD, Chen H, Ball DW. Regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by Notch signaling. J Clin Endocrinol Metab, Jul/2005;90(7):4350-6.  PMID: 15870121  

³  Wang YC, Gallego-Arteche E, Iezza G, Yuan X, Matli MR, Choo SP, Zuraek MB, Gogia R, Lynn FC, German MS, Bergsland EK, Donner DB, Warren RS, Nakakura EK. Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors. Endocr Relat Cancer, Mar/2009;16(1):267-79.  PMID: 18987169 

⁴  Wang YC, Zuraek MB, Kosaka Y, Ota Y, German MS, Deneris ES, Bergsland EK, Donner DB, Warren RS, Nakakura EK. The ETS oncogene family transcription factor FEV identifies serotonin-producing cells in normal and neoplastic small intestine. Endocr Relat Cancer, 2010;17(1):283-91.  PMID: 20048018 

Neuroendocrine Tumors of Unknown Primary

Dr. Nakakura and colleagues have found a straightforward solution to a challenging issue for patients with NETs.  Often patients are diagnosed with a NET; however, the primary site remains elusive.  Based on the small size, submucosal location, and outward growth pattern of ileum NETs, they hypothesized that most patients with NET of unknown primary tumor have an ileal primary tumor.¹  Indeed, despite a negative preoperative evaluation, surgical exploration identifies an ileal primary tumor in most cases.^1-3  Their studies show that the routine use of many other tests, such as capsule endoscopy, enteroclysis, double-balloon enteroscopy, and endoscopic ultrasonography, is unnecessary because they will not affect patient care and will only delay treatment. 

¹ Wang SC, Parekh JR, Zuraek MB, Venook AP, Bergsland EK, Warren RS, Nakakura EK. Identification of unknown primary tumors in patients with neuroendocrine liver metastases. Arch Surg. 2010 Mar; 145(3):276-80. PMID: 20231629 

² Wang SC, Fidelman N, Nakakura EK. Management of well-differentiated gastrointestinal neuroendocrine tumors metastatic to the liver. Seminars in Oncology. 2013 Feb; 40(1):69-74. PMID 23391114

³ Bergsland EK, Nakakura EK. Neuroendocrine tumors of unknown primary: Is the primary site really not known? JAMA Surg. 2014 Sep; 149(9):889-90. PMID: 25029597

Predictors of Lymph Node Metastases in Pancreatic Neuroendocrine Tumors

The significance of lymph node metastases in PNETs is controversial. Consequently, the role and extent of lymph node sampling in PNETs is not standardized.  Therefore, there is no consensus regarding the optimal surgical approach for PNETs.  Surgical options include pancreas-preserving procedures (enucleation, central pancreatectomy) versus standard resections (pancreaticoduodenectomy, distal pancreatectomy). 

Dr. Nakakura and colleagues hypothesized that the conflicting prognostic value of PNET lymph node metastasis might be due to inadequate evaluations of lymph nodes and difficulties predicting metastasis.  They found that lymph nodes are not evaluated in many major pancreatic resections for PNET and preoperative prediction of nodal metastasis is difficult.¹  Their findings suggest that enucleation of PNETs should be reserved for small insulinomas.  For other PNETs, surgeons should routinely sample lymph nodes, working closely with pathologists to maximize the number of lymph nodes identified in each specimen.  As a result of their study and that of others, the most recent NCCN guidelines for the management of PNETs have incorporated our recommendations and have affected patient management.² 

¹ Parekh JR, Wang SC, Bergsland EK, Venook AP, Warren RS, Kim GE, Nakakura EK. Lymph Node Sampling Rates and Predictors of Nodal Metastasis in Pancreatic Neuroendocrine Tumor Resections: The UCSF Experience With 149 Patients. Pancreas. 2012 Aug; 41(6):840-4.  PMID: 22781907  

²  http://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf (login/password required)