Elsevier

Pharmacology & Therapeutics

Volume 181, January 2018, Pages 49-75
Pharmacology & Therapeutics

Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers part 2: Neuroendocrine tumours, hepatocellular carcinoma, and gastro-intestinal stromal tumours

https://doi.org/10.1016/j.pharmthera.2017.07.006Get rights and content

Abstract

Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the cancer cell molecular biology has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents, being more specific to cancer cells, were expected to be less toxic than conventional cytotoxic agents.

However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings, illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies.

Targeted agents have provided clinical benefit in many GI cancer types. Particularly, some GI tumours are considered chemoresistant and targeted therapies have offered a new therapeutic base for their management. Hence, somatostatin receptor-directed strategies, sorafenib, and imatinib have revolutioned the management of neuroendocrine tumours (NET), hepatocellular carcinoma (HCC), and gastrointestinal stromal tumours (GIST), respectively, and are now used as first-line treatment in many patients affected by these tumours. However, these agents face problems of resistances and identification of predictive biomarkers from imaging and/or biology.

We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this second part, we will focus on NET, HCC, and GIST, whose treatment relies primarily on targeted therapies.

Introduction

Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the molecular biology of cancer cell has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies (mAb) or small molecule inhibitors (multikinase inhibitors [MKI]) directed against proteins that are specifically either overexpressed or mutated in cancer cells. These drugs were expected to be more specific to cancer cells and less toxic than conventional cytotoxic agents. However, their anticipated effects have sometimes been disappointing, due to either intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings or molecular subgroups (Holohan, Van Schaeybroeck, Longley, & Johnston, 2013). The identification of predictive biomarkers of response to these therapies, through deeper knowledge of GI tumour biology and phenotypic and molecular subtypes, has therefore become a major issue.

In this context, it appears crucial to gather updated clinical and translational data in a comprehensive review encompassing the lessons learned from the past as well as the yet unanswered questions regarding targeted therapies across the different GI cancer types. We propose a comprehensive two-part review providing a panoramic and chronological approach of the successes and failures of targeted agents that have reached phase III trials in GI cancers, to unravel the pharmacologic opportunities and future directions for these therapies in GI oncology. In the first part, we focused on adenocarcinomas and squamous cell carcinomas, for which targeted therapies are mostly used in combination with chemotherapy. We summarised the trajectories of targeted therapy development across these GI cancer types and highlighted how the clinical development of antiangiogenics, anti-EGFR, anti-HER2 agents, or, more recently, immune therapy, have followed strikingly different paths in terms of biological hypothesis, companion biomarkers, and refinement of their respective spectrum of sensitive tumours. In this second part, we focus on neuroendocrine tumours (NET), hepatocellular carcinoma (HCC), and gastrointestinal stromal tumours (GIST), whose treatment relies primarily on targeted therapies. For these selected GI tumours that were characterized by their poor sensitivity to chemotherapy, the advent of targeted therapies has been a complete shift of paradigm. These agents demonstrated their efficacy and offered a new therapeutic base for the management of these tumours. Hence, somatostatin receptor (SSTR)-directed strategies, sorafenib, and imatinib have revolutioned the management of NET, HCC, and GIST, respectively, and many patients affected by these tumours are now treated in first intent by targeted therapies only. However, these agents have to face problems of resistances and identification of predictive biomarkers from imaging and/or biology.

Section snippets

Epidemiology and therapeutic landscape

Digestive NET are a heterogeneous group of neoplasms arising from neuroendocrine cells that are organised as endocrine glands such as pancreas or scattered throughout the digestive tract. These rare tumours account for 1% of all digestive malignancies; nevertheless, NET are one of the most prevalent GI neoplasms after colorectal cancer, since they are usually slowly growing and associated with prolonged patient survival (Frilling et al., 2012, Frilling et al., 2014, Yao et al., 2008). The most

Epidemiology and therapeutic landscape

Hepatocellular carcinoma (HCC) represents > 90% of primary liver cancers and is a major health problem. It is the sixth most frequent cancer (780,000 new cases/year, > 80% in developing countries) and the second leading cause of cancer deaths (750,000 deaths/year) worldwide (Torre et al., 2015). In 90% of cases, HCC develops on underlying chronic liver disease (cirrhosis or chronic hepatitis), which can be caused by chronic hepatitis B (HBV) or C (HCV) virus infection, alcohol, inherited

Epidemiology and therapeutic landscape

GIST are mesenchymal tumours derived from Cajal cells or one of their precursors, developing in the majority of cases in the stomach (60%) and small bowel (20–30%), and more rarely in the rectum, colon, and esophagus, or mesentery, omentum, and retroperitoneum (extra-gastrointestinal GIST) (Emile et al., 2012, Miettinen and Lasota, 2006, Nishida et al., 2016). Although they are the most frequent mesenchymal tumours of the GI tract, they are yet relatively uncommon, with an estimated incidence

Disclosure/conflict of interest

CN: Celgene, Shire; LdM: Ipsen, Novartis, Pfizer; BR: Gilead, Novartis, Bayer; OM: Amgen, Astra-Zeneca, Bayer, Blueprint, Bristol-Myers-Squibb, Eli-Lilly, Lundbeck, Novartis, Roche, Pfizer, Servier; HK: Celgene, Baxalta; PR: Novartis, Ipsen, AAA, Pfizer; CT: Roche, Bayer, Amgen, Merck, Eli-Lilly.

References (306)

  • S.L. Chan et al.

    Personalized therapy for hepatocellular carcinoma: Where are we now?

    Cancer Treatment Reviews

    (2016)
  • A.L. Cheng et al.

    Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial

    The Lancet Oncology

    (2009)
  • M. Debiec-Rychter et al.

    KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours

    European Journal of Cancer

    (2006)
  • R.P. Dematteo et al.

    Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: A randomised, double-blind, placebo-controlled trial

    Lancet

    (2009)
  • G.D. Demetri et al.

    Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): An international, multicentre, randomised, placebo-controlled, phase 3 trial

    Lancet

    (2013)
  • G.D. Demetri et al.

    Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial

    Lancet

    (2006)
  • R. Dhanasekaran et al.

    Clinical implications of basic research in hepatocellular carcinoma

    Journal of Hepatology

    (2016)
  • M. Ducreux et al.

    Bevacizumab combined with 5-FU/streptozocin in patients with progressive metastatic well-differentiated pancreatic endocrine tumours (BETTER trial)—a phase II non-randomised trial

    European Journal of Cancer

    (2014)
  • A.G. Duffy et al.

    Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma

    Journal of Hepatology

    (2017)
  • S. Farag et al.

    Clinical characteristics and treatment outcome in a large multicentre observational cohort of PDGFRA exon 18 mutated gastrointestinal stromal tumour patients

    European Journal of Cancer

    (2017)
  • G.K. Abou-Alfa et al.

    Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (alliance)

    Journal of Clinical Oncology

    (2016)
  • A. Agaimy

    Gastrointestinal stromal tumors (GIST) from risk stratification systems to the new TNM proposal: More questions than answers? A review emphasizing the need for a standardized GIST reporting

    International Journal of Clinical and Experimental Pathology

    (2010)
  • A. Agaimy et al.

    V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumours

    Journal of Clinical Pathology

    (2009)
  • H.K. Ahn et al.

    Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours

    British Journal of Cancer

    (2013)
  • L.B. Anthony et al.

    Impact of previous somatostatin analogue use on the activity of Everolimus in patients with advanced neuroendocrine tumors: Analysis from the phase III RADIANT-2 trial

    Neuroendocrinology

    (2015)
  • M. Appetecchia et al.

    Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumours, current aspects and new perspectives

    Journal of Experimental & Clinical Cancer Research

    (2010)
  • J. Arrondeau et al.

    Sorafenib exposure decreases over time in patients with hepatocellular carcinoma

    Investigational New Drugs

    (2012)
  • A. Asnacios et al.

    Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: Results of a multicenter phase 2 study

    Cancer

    (2008)
  • M. Azizi et al.

    Home blood-pressure monitoring in patients receiving sunitinib

    The New England Journal of Medicine

    (2008)
  • R. Baldelli et al.

    Somatostatin analogs therapy in gastroenteropancreatic neuroendocrine tumors: Current aspects and new perspectives

    Frontiers in Endocrinology

    (2014)
  • S. Bauer et al.

    Emerging agents for the treatment of advanced, Imatinib-resistant gastrointestinal stromal tumors: Current status and future directions

    Drugs

    (2015)
  • O.E. Bechter et al.

    Open-label, phase IIIb, multicenter, expanded access study of everolimus in patients with advanced neuroendocrine tumors (NET)

    Journal of Clinical Oncology

    (2013)
  • N. Benslama et al.

    Prediction of response to everolimus in neuroendocrine tumors: Evaluation of clinical, biological and histological factors

    Investigational New Drugs

    (2016)
  • E.K. Bergsland

    Combined mammalian target of rapamycin and vascular endothelial growth factor pathway inhibition in pancreatic neuroendocrine tumors: More than the sum of its parts?

    Journal of Clinical Oncology

    (2015)
  • C.D. Blanke et al.

    Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT

    Journal of Clinical Oncology

    (2008)
  • C.D. Blanke et al.

    S0502: A SWOG phase III randomized study of Imatinib, with or without bevacizumab, in patients with untreated metastatic or Unresectable gastrointestinal stromal tumors

    The Oncologist

    (2015)
  • C.D. Blanke et al.

    Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033

    Journal of Clinical Oncology

    (2008)
  • J.Y. Blay et al.

    Management of gastrointestinal stromal tumour: Current practices and visions for the future

    Oncology

    (2015)
  • J.Y. Blay et al.

    Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: The French sarcoma group

    Journal of Clinical Oncology

    (2007)
  • A. Blesius et al.

    Neoadjuvant imatinib in patients with locally advanced non metastatic GIST in the prospective BFR14 trial

    BMC Cancer

    (2011)
  • L. Bodei et al.

    Yttrium-labelled peptides for therapy of NET

    European Journal of Nuclear Medicine and Molecular Imaging

    (2012)
  • L. Bodei et al.

    Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: The value and limitations of clinical factors

    European Journal of Nuclear Medicine and Molecular Imaging

    (2015)
  • J.B. Bomanji et al.

    (1)(1)(1)In-DTPA(0)-octreotide (Octreoscan), (1)(3)(1)I-MIBG and other agents for radionuclide therapy of NETs

    European Journal of Nuclear Medicine and Molecular Imaging

    (2012)
  • M. Bouattour et al.

    Negative trials for foreseeable safety reasons in advanced hepatocellular carcinoma: How long are we going to take lightly pharmacokinetics of tyrosine kinase inhibitors?

    Journal of Clinical Oncology

    (2015)
  • P. Boudou-Rouquette et al.

    Variability of sorafenib toxicity and exposure over time: A pharmacokinetic/pharmacodynamic analysis

    The Oncologist

    (2012)
  • C. Bousquet et al.

    Clinical review: Current scientific rationale for the use of somatostatin analogs and mTOR inhibitors in neuroendocrine tumor therapy

    The Journal of Clinical Endocrinology and Metabolism

    (2012)
  • M. Brahmi et al.

    Masitinib for gastrointestinal stromal tumors

    Expert Opinion on Orphan Drugs

    (2016)
  • P. Brazeau et al.

    Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone

    Science

    (1973)
  • B. Brieau et al.

    High risk of myelodysplastic syndrome and acute myeloid leukemia after 177Lu-octreotate PRRT in NET patients heavily pretreated with alkylating chemotherapy

    Endocrine-Related Cancer

    (2016)
  • J. Bruix et al.

    Liver cancer: Approaching a personalized care

    Journal of Hepatology

    (2015)
  • Cited by (9)

    View all citing articles on Scopus

    Associate editor: B. Teicher

    View full text