Neuroendocrine tumours form from cells that release hormones into the blood in response to a signal from the nervous system. These tumours have unique characteristics that allow for the development of radiopharmaceuticals, which are drugs that contain a radioactive substance that can be used to both diagnose cancer via imaging and treat disease. However, not all patients will benefit from treatment with radiopharmaceuticals. Therefore, we need to identify clinical and imaging-based markers that may distinguish good responders from poor responders prior to treatment, so we can identify patients that would most benefit from this therapy. As images of the tumour are taken prior to treatment, they may provide valuable insight into the underlying causes of the disease. Radiomics is the process of extracting quantitative features from medical images to predict outcomes and typically these features are not visible to a clinician’s eye. In this study, we will extract features from pre-treatment medical images and combine these with clinical indicators to predict progression-free survival (length of time that a patient lives with cancer but it does not get worse) and overall survival. This non-invasive software model will allow us to better determine the likely course of the disease and will aid clinicians in identifying patients at a lower risk of treatment failure who will most benefit from this therapy. This will allow for more personalized treatment for patients with neuroendocrine tumours.

Neuroendocrine tumours (NET), are increasing in incidence around the world, including Canada. Most NETs are diagnosed as low-grade and are relatively slow-growing tumours. Nonetheless, they commonly present as advanced (metastatic) and incurable cancers which will result in death over time. Some of these NETs will also cause the overproduction and release of hormones, causing “carcinoid syndrome” which can result in severe symptoms for the patient. The main treatment for these tumours is a type of inhibitory hormone injection called somatostatin analogues (SSA). These slow tumour growth and relieve carcinoid syndrome. Unfortunately, despite SSA treatment usually working, most patients will experience tumour growth over time. Nonetheless, SSA are continued for the long term. After this tumour growth, specialised targeted radiotherapy (PRRT) is used; however, it is not known if continuing SSA after PRRT is worthwhile or not. These injections can cause side effects and are expensive for the healthcare system. Therefore, it is important to know whether their use after PRRT is helpful for the patient. In the STOPNET trial, we will stop SSA injections in some patients following PRRT and compare tumour growth, side effects and quality of life with patients in whom the SSA injections are continued.

Non-resectable metastatic patients with neuroendocrine tumors benefit from an injected radioactive treatment, 177Lu-peptide receptor radionuclide therapy (PRRT) (recently Health Canada-approved), with longer time before progression and longer survival. The protocol includes a slow infusion of amino acids (arginine/lysine) IV before, during and after treatment, a substance which presumably decreases kidney accumulation of the therapy agent. This however causes the most frequent side effects of this therapy, nausea and vomiting, and increases time spent in hospital, complexity of scheduling, and treatment costs. The reasons for the use of amino acids come from old cases of patients treated with a different version of PRRT. Validation that amino acids decrease renal accumulation was also done with another different (imaging) agent. Moreover, PSMA-radionuclide therapy (PRLT) such as 177Lu-PSMA-617 is a different therapy (for prostate cancer) with similar or higher accumulation in the kidneys, yet very little kidney toxicity. We conclude that little is known regarding the true efficacy and necessity of amino-acid infusion for 177Lu-PRRT.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are highly heterogeneous diseases with a variable patient prognosis. The current grading system of GEP-NENs is primarily based on the proliferation status of the tumors. While this grading has some prognostic value, it can be subjective, and variable between different centers. Thus, there is an urgent need to identify superior methods to stratify GEP-NENs.

In this study, first, we aim to construct a comprehensive tissue microarray (TMA) from archival tissue from patients with GEP-NENs. This TMA will include 600 samples, in duplicate, from GEP-NENs from various primary sites (pancreas, stomach, small intestine, colon, and rectum), as well as patients with disease recurrence, and metastasis. We foresee that this GEP-NEN-TMA will facilitate the discovery of better prognostic markers, a better understanding of the biology of NENs, and the identification of therapeutic vulnerabilities. Herein, we propose to examine the prognostic value of two molecular subtypes, MLP and YAP-OFF, that our groups and others have shown to be involved in the progression of NENs. Notably, these molecular subtypes are currently not used in clinical practice, and this will be the first study to examine their clinical utility. Incorporating molecular subtypes in diagnosing patients with NENs can lead to better classification and prognosis, patient-specific treatment, and improve quality of life and overall survival.

The somatostatin receptor subtype 2 (SSTR2) expressed by many neuroendocrine tumors (NET) is targeted by peptide receptor radionuclide therapy (PRRT) with radiopharmaceuticals, such as 177Lu-DOTATATE (LuTate). Although LuTate-PRRT is the most successful targeted therapy for NET, it does not deliver complete remission, and many NET patients with low SSTR positivity are ineligible for PRRT. Recently, we identified that two different patient -derived NET cell lines specifically upregulate SSTR2 expression for a period of 14 days after a short exposure to small doses of chemotherapeutic drugs. Moreover, this results in a greater uptake of LuTate and better therapeutic impact as compared to cells that were not exposed to chemotherapy.

The short-term goals of this project are to validate this combination approach in vivo with these NET cell lines-derived tumors in mice and in multiple Lung NET patient-derived tumor explants ex-vivo.

The long -term goal is to provide a convincing pre-clinical evidence that will permit launch of clinical trials to examine the efficacy of these combination approach in NET patients to not only improve their response to LuTate but also make more NET patients eligible for LuTate PRRT.

The only approved therapy for advanced LNENs is everolimus, which is associated with low response rates and important toxicities. Temozolomide based chemotherapy has been explored in gastroenteropancreatic NETs demonstrating efficacy. However, it has not been studied as treatment option for well differentiated LNENs in prospective trials or as large real world data, given the rarity of this disease. Therefore, collaborative efforts like this project is an important opportunity to clarify a role for treatments in well differentiated LNENs, that have demonstrable activity in NENs of other sites of origin.

High-grade neuroendocrine (NET) lung tumors represent around 23% of all neuroendocrine cancers, and constitute small cell lung carcinoma and large cell neuroendocrine carcinoma. These are clinically aggressive tumors diagnosed in heavy-smoking patients, and have poor prognosis with limited treatment options. Recently, immunotherapy has emerged as a new standard of care by harnessing the body’s immune system to treat several aggressive malignancies, including lung cancer. Given the scarcity of therapeutic interventions to treat NETs, and the success of immunotherapy in treating smoking-associated cancers, certainly makes it as a viable therapeutic option. Here we aim to better understand how the tumor immune landscape will influence the response to immunotherapy in NET patients. We will leverage pathological slides to obtain PD-L1 expression, CD8 localization and radiological data to build a digital biomarker in order to identify immune microenvironments based on CD8 inflitration.

18F-DOPA PET/CT, 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT are imaging techniques that can identify the location of neuroendocrine tumors (NETs) by different mechanism: 68Ga-DOTATATE binds to somatostatin receptors, 18F-DOPA relates to increased amino acid uptake in NETs, and 18F-FDG relates to increased glucose uptake in NETs.  18F-DOPA and 68Ga-DOTATATE have a reported high accuracy in identifying NETs, although there have been no reported direct comparisons of the same lesions in the same patients. The goal of our study is to evaluate patients with metastatic NETs with all three tracers to determine the prevalence of NET lesions that are 68Ga-DOTATATE avid (concordant with 177Lu-DOTATATE therapy) versus non-68Ga-DOTATATE avid (discordant with therapy).  Non-68Ga-DOTATATE avid lesions will be identified using 18F-DOPA (for well-differentiated lesions) and 18F-FDG (for poorly-differentiated lesions). It is expected that patients with discordant lesions will have poorer response to PRRT.

Neuroendocrine tumors (NETs) of the pituitary, stomach, duodenum, pancreas and rectum have been recognized to be composed of different cell types that have distinct growth patterns, different invasiveness and variable responses to therapies. This study will examine the cell types that comprise neuroendocrine tumors of the appendix to determine if there are multiple different tumor types that make different hormones and have different clinical and biologic features. The information obtained from this study will allow re-classification of appendiceal NETs into categories that may have different requirements for aggressive surgery and post-surgical treatments and will provide unique circulating biomarkers to monitor patients for recurrent disease.

The incidence of neuroendocrine tumors (NET) is increasing and due to delayed diagnosis, patients have few conventional therapeutic options. Peptide receptor radionuclide therapy (PRRT) is a targeted therapy that directly delivers radioactive drug to the docking sites or somatostatin-receptors on the NET cells. PRRT is recommended for many types of NET but there is a need to improve its therapeutic efficacy. Based on our recent in vitro data with NET cells growing in culture medium, we will examine in animal model of NET whether pre-treatment with low doses of chemo drugs can upregulate these receptors so that a subsequent PRRT treatment will deliver a one-two knockout punch to the tumors without causing adverse incidental toxicity to the animal. This approach will not only improve therapeutic efficacy of PRRT but also allow previously ineligible NET patients become eligible to receive PRRT.

The variable clinical outcome of patients with G2 and G3 well differentiated GEP-NETs makes the selection of an optimal treatment strategy challenging. Therefore the prospective validation of the clinical impact of addition of 18F-FDG PET/CT imaging to 68Ga-DOTATATE imaging to planned clinical treatment of patients with G2-G3 well differentiated GEP-NETs, along with the validation of novel comprehensive imaging biomarkers is critical to develop new prognostic tools that could help individualizing patient management deciding which patients might potentially be managed and treated “less aggressively” with observation, somatostatin analogs or peptide receptor radionuclide therapy (PRRT) and which might need more “aggressive” approach systemic therapies such as chemotherapy.

About 40% of patients with small bowel tumors develop carcinoid syndrome (CS) but it takes multiple years before a diagnosis is made. Pasieka et al. reported significant cognitive impairment in NET patients with CS. We plan a prospective, multicentre study to test the hypothesis that somatostatin analogs therapy improves the cognitive dysfunction in these patients.

We propose a pilot feasibility study to assess the research protocol, data collection instruments, recruitment strategies, research techniques in preparation for the larger study. The pilot will enroll 10 CS patients in 4-5 tertiary Canadian cancer centres. We will test with researchers whether the protocol is workable, recruitment of subjects achievable, identify logistical problems with data collection, adequacy of cognitive assessment tools and patients’ adherence to the re-test schedule. Preliminary data collected will help researchers concentrate the protocol on a narrow spectrum of specific cognitive dysfunctions.

Neuroendocrine tumors (NETs) are increasingly common cancers that are hard to diagnose and monitor. Some NET patients wait many years before getting an accurate diagnosis, giving their cancer time to spread. Even after diagnosis, patients with aggressive disease may need frequent imaging follow-up to plan their care. Earlier diagnosis and easier monitoring would allow faster access to effective treatment. microRNAs are genetic control molecules that are present in all human cells. Some microRNAs are also excellent disease markers because they are found in only one cell type.

We believe we have found a single microRNA that is only found in neuroendocrine and neuroendocrine tumor cells. In this proposal, Drs. Renwick and Singh combine their expertise in microRNA detection and NET clinical care to develop a simple blood test to diagnose and monitor all NETs. This simple test is expected to improve the lives of Canadian NET patients by enabling faster access to life-preserving treatment.

Although used in other tumor sites, immunotherapy has not shown great clinical results for patients with neuroendocrine tumors (NETs). NETs typically have a low rate of genetic mutations, making it difficult for the body to mount an effective immune response. Radiation has been shown to cause DNA breaks and will stimulate an immune response to tumors. Therefore, combining radiation and immunotherapy may produce improved results in NETs patients.

This study aims to identify how radiation may cause immune-related changes in neuroendocrine tumors, which may be harnessed to increase the effectiveness of immunotherapy agents. Patients will be selected to receive high-dose radiation to a site of cancer, which will be biopsied (sampled) afterwards to analyze what changes radiation may be effecting on the cancer cell or surrounding tissue. If radiation is proven to cause immune-related changes, it would provide evidence to combine radiation and immunotherapy in future clinical trials.

DIPNECH is a recently described respiratory disease defined by the proliferation of several foci of neuroendocrine cells affecting both lungs, and leading to airway obstruction, development of multiple neuroendocrine tumors, and sometimes to respiratory failure. Unfortunately, the disease is poorly characterized both at clinical and molecular levels, which explains why the current clinical criteria are ill-defined and the condition under recognized and misdiagnosed. Furthermore, there is no standard treatment for the patients symptomatic of the disease or progressing towards respiratory failure. It is therefore urgent to better understand the pathophysiology and the molecular alterations underlying the development of this condition in order to develop animal and in vitro models to identify potential targets that may lead to new treatments.  The  study proposes to refine the clinical diagnostic criteria and to analyze the key-genomic events involved in the development of DIPNECH.

Neuroendocrine tumours can vary widely in behaviour, but Grade 3, poorly-differentiated neuroendocrine carcinomas (NECs) are aggressive. Patients with metastatic NECs, on average, live for less than a year. Chemotherapy is often used for Grade 3 NECs but has many side effects and generally stops working after several months. We are trialing immunotherapy (using a drug called avelumab) to see whether this drug is effective in controlling disease in patients with metastatic NEC. We plan to look at aspects of the tumour tissue (mutational load, T cell repertoire) in order to determine whether this can help predict responses to immunotherapy in Grade 3 NECs.

Neuroendocrine tumours (NETs) often present at an advanced stage when cure is not possible with surgery. For patients suffering from advanced NETs, peptide receptor radionuclide therapy (PRRT) is a NET-specific treatment involving the administration of a radioactive drug that specifically recognizes these tumors and delivers a payload of radiation that can destroy them. Although PRRT is one of the most effective treatments against NETs, cure remains rare because the amount of radiation that could be delivered to the tumours is limited by the side-effects caused to healthy organs. Our team of cancer researchers, composed of a biologist and a nuclear medicine physician, will examine if a novel and promising approach of co-administering a medication (called an inhibitor of the PARP enzyme) along with PRRT can improve its efficacy without augmenting toxicity. Our research has therefore the potential to significantly improve the outcome of patients suffering from NETs.

Neuroendocrine tumors (NETs) are a diverse group of slow-growing tumors arising from a variety of different sites within the body, mostly from the gastro-intestinal system. These tumors present some diagnostic challenges: NETs are often diagnosed late in the disease and sometimes it is hard to determine locations where the disease has spread. There are many different types of therapies for these tumors and sequencing these therapies is a major current consideration in the clinical management of NETs. Depending on their tumor grade, NETs can progress rapidly, so it is important to accurately identify and characterize the tumors so that they can be treated most appropriately. The purpose of this study is to test a combination of two functional imaging techniques to characterize NET. This study will determine how the information gained from this imaging affects the choice of treatment therapy. It also measures how changes in the therapy as a result of the imaging impact the patient.