ALK+ lung cancer and the Blood-Brain Barrier (BBB) A concise guide

Transcription

1 ALK+ lung cancer and the Blood-Brain Barrier (BBB) A concise guide

2 Contents Section Page number Section 1: Lung cancer and ALK+ NSCLC 3 Section 2: The Blood-Brain Barrier (BBB): What and why? 4 Section 3: Behind the Blood-Brain Barrier (BBB): The function of the barrier 5 2

3 Section 1: Lung cancer and ALK+ NSCLC Lung cancer Lung cancer is the most common type of cancer worldwide. There are more than 1.8 million new cases of lung cancer each year, 1 which equates to 13% of total cancer cases. 2 It is also more deadly than any other cancer, having resulted in 1.59 million deaths in There are two main types of lung cancer small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). SCLC is relatively uncommon, occurring in about 15% of lung cancer patients, while NSCLC occurs in the majority of the remaining lung cancer cases. 4 Within NSCLC, there are several further subtypes driven by different receptors and genetic mutations, including anaplastic lymphoma kinasepositive (ALK+) NSCLC. Alveoli Lung cancer tumours FACT 1: More people die of lung cancer worldwide than of breast, prostate and colorectal cancers combined 5 Worldwide, approximately 90,000 new cases of ALK+ NSCLC are diagnosed each year, which amounts to more than 5% of the total new lung cancer cases. 6 The anaplastic lymphoma kinase (ALK) gene plays an important role in the cells of the nervous system and its expression is normally under strict genetic control. 7 ALK+ NSCLC is caused by activating mutations in the ALK gene, which cause it to fuse with another gene (most often EML4) to create an ALK-fusion protein. 8 Unlike other forms of lung cancer, ALK+ NSCLC is most commonly diagnosed in younger people with a light or nonsmoking history. 9 FACT 2: Researchers have identified 15 unique mutations and biomarkers that are responsible for tumour growth in NSCLC 10 3

4 Section 2: The Blood-Brain Barrier (BBB): What and why? FACT 3: The most common cause of brain metastasis in men is lung cancer, and women are expected to follow this trend shortly 11 Blood-Brain Barrier (BBB) and lung cancer Patients with this distinct form of lung cancer are at high risk of developing brain metastases. As many as 60% of anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALK+ NSCLC) patients who are treated with the current standard of care see their tumours spread to the brain within a year. 12 This means that treatments for the disease need to be able to reach tumours in both the lungs and the brain. The ability to effectively treat brain metastases is extremely important, as tumours that spread to the brain are particularly devastating to patients. They can result in the loss of vital functions such as vision or movement, impact mental performance or cause changes in personality and behaviour. 13 Furthermore, compared to other sites, brain metastases are associated with a significant reduction in quality of life and life expectancy. 14 Brain Lungs Spinal cord Tumours Lung cancer cells can spread to the brain (brain metastases) Nerves FACT 4: Around 1 in 3 people with brain metastases will have no symptoms. Symptoms are dependent upon which part of the brain is affected, how many tumours are present and the person s general health 15 Structure of the Blood-Brain Barrier (BBB) Cell nucleus Blood-Brain Barrier cells The BBB is a tightly-joined network of cells lining the blood vessels in the brain and spinal cord, which protects the brain and Central Nervous System by preventing the entry of certain harmful molecules. 16 Brain metastases can be difficult to treat because most anaplastic lymphoma kinase (ALK) inhibitors are able to cross the BBB, but are pumped out by active efflux so the concentration is low in the brain. 17 Blood Tight junctions between cells (gaps between cells are <1nm) Basement membrane BRAIN 4

5 Section 3: Behind the Blood-Brain Barrier (BBB): The function of the barrier FACT 5: The total length of all the blood vessels in the BBB is 600 km. That s the equivalent of 2000 stacked Eiffel Towers! 18 BLOOD 1 Some molecules can cross by diffusion 2 Some molecules can fit through the tight junctions between cells 3 Some larger molecules are transferred across by carrier proteins How the Blood-Brain Barrier (BBB) works The BBB controls which molecules can enter the brain from the blood, for example, according to their size. The BBB stops some molecules entering the brain entirely. There are a few different ways a molecule can cross the BBB, for example: BLOOD-BRAIN By diffusion Through the tight gaps between the BBB cells (for smaller molecules) BRAIN Carrier proteins By carrier proteins (for larger molecules) 19 Tight junction The active efflux system Even if a drug is able to cross the BBB, it may be pumped out of the brain and wider Central Nervous System by a mechanism called active efflux. Active efflux occurs when special proteins recognise some of the molecules that have crossed the BBB and transport them back into the blood. 20 Only the molecules that can both cross the BBB and avoid the active efflux system are able to treat brain metastases. FACT 6: More than 90% of cancer morbidity (poor quality of life, pain, impaired organ function) and cancer deaths are directly related to metastasis 21 Active efflux protein BLOOD BLOOD-BRAIN BARRIER BRAIN 5

6 References 1 GLOBOCAN GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in [Available at: iarc.fr/pages/fact_sheets_cancer.aspx Last accessed ]. 2 GLOBOCAN GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in [Available at: iarc.fr/pages/fact_sheets_cancer.aspx Last accessed ]. 3 World Health Organization. Cancer. [Available at: en/ Last accessed ]. 4 Barzi A and Pennell NA. Targeting angiogenesis in non-small cell lung cancer: agents in practice and clinical development. EJCMO. 2010; 2(1): GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in [Available at: sheets_cancer.aspx Last accessed ]. 6 Roche data on file. 7 Solomon Benjamin, et al. ALK Gene Rearrangements: A New Therapeutic Target in a Molecularly Defined Subset of Non-small Cell Lung Cancer. Journal of Thoracic Oncology. 2009; 4(12): Choi Young Lim, et al. Identification of Novel isoforms of the EML4-ALK Transforming Gene in Non-Small Cell Lung Cancer. Cancer Research 2008; 68: About Health. ALK Positive Lung Cancer Definition and Treatment. [Available at: lungcancer.about.com/od/targeted-therapy-lung- Cancer/a/ALK-Lung-Cancer.htm Last accessed ]. 10 Molecular Profiling of Lung Cancer [Available at: lung-cancer Last accessed ]. 11 International RadioSurgery Association. Metastatic Brain Tumours. [Available at: metastatic_tumors.html Last accessed ]. 12 Gainor JF, et al. Alectinib Salvages CNS Relapses in ALK-Positive Lung Cancer Patients Previously Treated with Crizotinib and Ceretinib. Journal of Thoracic Oncology. 2015; 10: Wong J, et al. Quality of life in brain metastases radiation trials: a literature review. Current Oncology. 2008; 15(5): Roughley A, et al. Impact of Brain Metastases on Quality of Life and Estimated Life Expectancy in Patients with Advanced Non-Small Cell Lung Cancer. Value in Health. 2014; 17: A Sawaya Raymond. Considerations in the Diagnosis and Management of Brain Metastases. Oncology. 2001; 15: Abbott Joan N, et al. Astrocyte-endothelial interactions at the blood-brain barrier. Nature Reviews Neuroscience. 2006; 7: Weickhardt AJ, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. Journal of Thoracic Oncology. 2012; 7: Wong Andrew D, et al. The blood-brain barrier: an engineering perspective. Frontiers in Neuroengineering. 2013; 6: Partridge William M. Drug transport across the blood-brain barrier. Journal of Cerebral Blood Flow & Metabolism. 2012; 32; Partridge William M. Drug transport across the blood-brain barrier. Journal of Cerebral Blood Flow & Metabolism. 2012; 32; American Cancer Society. Unlocking the Mysteries of Metastasis. [Available at: org/cancer/news/expertvoices/post/2013/01/23/ unlocking-the-mysteries-of-metastasis.aspx Last accessed ]. 6