Lidsky,+Taylor

=__Mesothelioma__=

**Introduction to Pat's Cancer**
Pat is a beloved mother and grandmother in her 60’s. She lives with her husband in suburban New York, and stopped working in the late 1960’s to raise their four children. As a child she was exposed to asbestos while attending elementary school, and now Pat has developed mesothelioma as a result. Mesothelioma is a rare cancer of the mesothelium, the protective lining that covers many of the body’s internal organs. This cancer can affect many areas of the body but is most commonly originated in the pleura, the outer lining of the lungs, which is where Pat’s cancer has manifested. Most cases are caused by asbestos exposure, but other toxins can also influence risk, and mutations at the BAP1 (BRCA1-associated protein 1) locus have been shown to increase susceptibility to mesothelioma. The BAP1 gene codes for a transcription repressor required to silence genes involved in cell fate determination and stem cell pluripotency. Pat’s family carries this mutation, so she and her siblings inherited it from their parents. However, Pat was the only one to be exposed to asbestos and thus hers is an isolated case.

As with most cases of this disease, Pat’s mesothelioma did not begin to produce symptoms until decades after her exposure to asbestos. She recently began experiencing shortness of breath and chest pain, and was given a chest X-ray that revealed thickening of the pleura and the presence of fluid between the lungs and the chest wall. Her doctor took a sample via thoracentesis, a technique where a long needle is inserted into the patient’s abdomen to withdraw fluid. The cells in this fluid were examined by cytopathologists and found to be abnormal. Pat’s doctor then performed an MRI scan and found several small tumor masses in the pleural lining of one of her lungs. At this point, Pat’s cancer is localized within the lung and is thus classified as stage 1, the stage with the best prognosis and widest range of available treatment options.

Mesothelioma as a whole is a very aggressive disease; the average 1 year survival rate after diagnosis for all patients is about 40%, and the average 5 year survival rate is about 10%. Since Pat has pleural mesothelioma rather than the rarer and more aggressive peritoneal mesothelioma, which attacks the lining of the abdomen rather than the lungs and chest cavity, she has a comparatively good prognosis. In addition, Pat’s cancer cells are epithelioid rather than sarcomatoid, which also improves her prognosis because the former are generally easier to treat. Epithelioid mesothelioma cells have a regular shape and a tendency to clump together, whereas sarcomatoid cells are shaped irregularly, don’t stick together as strongly, and thus metastasize much more quickly. However, her disease is still typically fatal within less than 2 years of diagnosis for someone her age.

Interestingly, the aggressiveness of the disease is not the only important factor contributing to the poor survival prognoses for mesothelioma patients; equally troublesome is the difficulty in diagnosis due to how common many mesothelioma symptoms are across a range of other respiratory problems, such as the flu and pneumonia. This often leads to misdiagnosis and/or failure to recognize the disease until it reaches later stages. Fortunately for Pat, she was contacted by her old school and notified of her exposure to asbestos several years before her symptoms began, so she was able to inform her doctors. This knowledge helped them immensely in narrowing down her diagnosis, so her cancer was detected relatively early. This, too, improves her prognosis compared to other mesothelioma patients of a similar age.

Pat’s cancer has not yet metastasized and spread into other tissues besides her lungs, but this possibility is of great concern to her doctors. Pleural mesothelioma has the tendency to spread to the rest of the lungs, abdominal cavity, lymph nodes, and the heart, and can do so very quickly. If it reaches these other tissues, it can worsen the symptoms Pat has been feeling and can cause pneumonia-like problems such as fatigue and weight loss, as well as making her cancer much more difficult to treat and diminishing her chances for remission. Her recovery depends on receiving aggressive treatment as quickly as possible, before it has a chance to spread.

Molecular Basis
Asbestos fibers can cause many types of lung damage, including on a molecular level due to their ability to adhere to DNA and introduce reactive oxygen species (free radicals), causing chromosomal breaks. This type of large-scale genomic damage puts the cells of the lungs and pleura at an incredibly high risk for mutagenesis and dysregulation of gene expression, drastically increasing the victim’s susceptibility to developing cancer. A large subpopulation of Pat’s tumor is comprised of clones that arose from a cell subjected to such a chromosomal break; the break occurred near the TP53 gene and resulted in its translocation to the end of another chromosome, where it was placed in a transcriptionally repressed region.

This gene codes for the p53 protein, which is normally expressed in response to cytotoxic damage and acts as a transcription factor that tells the cell to express apoptosis-inducing proteins. Placing this gene in a heterochromatic area resulted in drastically lowered levels of p53 expression in the cell. In addition, since Pat was born with a mutated BAP1 allele and thus had decreased levels of this transcription repressor, her cells were already at risk for inappropriate growth and proliferation. The combination of both of these losses has allowed these cells to bypass apoptotic signals and continue to survive and divide, even in the presence of cytotoxic damage. Cisplatin targets these cells that should be entering apoptosis by creating DNA crosslinks that prevent DNA polymerase from reaching the nucleotides. This stops the cells from replicating their DNA and going through cell division, forcing them to arrest the cell cycle and undergo cell death. Thus, it bypasses the failure of natural tumor suppressing mechanisms, like the p53 pathway, and stops tumor cells from proliferating any further.

Among these rapidly proliferating cells are a group that have upregulated their expression of the growth factor VEGF above normal levels, activating the formation of new blood vessels around the tumor. In normal cells, lack of oxygen induces the production of HIF (hypoxia induced factor), which stimulates the cell to produce and secrete VEGF, but a mutation in the promoter of the VEGF gene has allowed Pat’s cancer cells to bypass the need for HIF and express VEGF constitutively. The extensive angiogenesis initiated by this change has supplied the tumor with large amounts of oxygenated blood and nutrients that it needs to continue growing in spite of the influence of contact inhibition, or signals from adjacent cells that tell the cell it is surrounded and should stop dividing. In addition, these new blood vessels are marked by growth abnormalities that make them prone to hemorrhage. A cancer drug called Bevacizumab is designed to block the effects of VEGF and prevent further angiogenesis. This drug acts as an antibody that binds to VEGF and targets it for destruction by the immune system, so even when cancer cells produce inappropriate amounts of this growth factor, it is broken down before it can stimulate blood vessels to start growing. Unfortunately, since VEGF is also required for repairing blood vessels during wound healing, bevacizumab cannot be administered within 28 days of surgery or the patient’s surgical incisions will not heal properly.

Luckily, the cells in this genetically unstable and rapidly proliferating tumor are not at high risk for metastasis, for several reasons. They continue to express normal levels of the adhesion protein E-cadherin, so they are able to stay as firmly attached to one another and the extracellular matrix as they would in normal tissue. Mutations in E-cadherin and other cell-to cell adhesion proteins are usually what cause metastasis and bring mesotheliomas out of stage 1. These adhesion deficiencies are also exacerbated by the abnormal shape of the sarcomatoid mesothelioma cell type, so again, Pat is lucky that her cancer cells are epithelioid in shape. However, as the tumor continues to grow uncontrollably and form abnormal vascular networks, the risk of metastasis increases steadily, so it’s still crucial that she is treated as soon as possible.

Diagnosis and Treatment
Because only 1 in every 100,000 Americans is diagnosed with mesothelioma each year, there are no screening programs recommended for the general public. Most patients aren’t diagnosed until they start experiencing severe symptoms and the disease has progressed to stage II or III. If a pleural effusion is detected, doctors will usually do an imaging test, such as a PET scan, to look for the presence of a tumor or cancerous cells. If the results of the imaging test raise concern, then the doctor will usually take a sample of the fluid, or a biopsy of the tumor (if a tumor is found) and the cells in this sample will be analyzed in a pathology lab. The pathologists can use a number of techniques to categorize the cells, including immunohistochemical assays and DNA microarrays that can distinguish mesothelioma cells from other types of cancer, as well as visually assessing them under a microscope, which is important in determining whether the cells are epithelioid or sarcomatoid. Another diagnostic assay recently made available is MesoMark®, a blood test that detects soluble mesothelin-related peptides (SMRPs), which are tumor differentiation antigens that are overexpressed on mesothelioma cells, and thus often present at high levels in patient serum. Once all the diagnostic information from these various tests and techniques has been collected, doctors use it to assign the cancer a stage, which is usually the deciding factor when choosing a course of treatment.

The standard of care for stage I pleural epithelioid mesothelioma in a patient such as Pat is surgical resection. There are several surgical options available to her doctors: they can do a wide local excision, removing the cancer as well as a sizable portion of the healthy tissue around it, a pleurectomy and decortication, removing the tissue lining the lungs and chest, or a palliative pleurodesis in which they drain the pleural effusion and create scarring in the pleura that prevents fluid buildup from returning. Because Pat’s lung function is less than ideal and a wide excision would remove a considerable portion of her lung tissue, this option is too risky. Removing the majority or entirety of one lung can be a fatal surgery in as many as 30% of cases. Keeping the pleurodesis in mind as a palliative measure in case resectioning is unsuccessful, Pat’s doctors decide to perform the pleurectomy and decortication, hoping it will be sufficient to eradicate her cancer while causing minimal harm. Operative mortality for this surgery is less than 2%, so they are confident that she will survive and recover well.

For most stage I mesothelioma patients, surgical resectioning is deemed an adequate treatment without the need for adjuvant therapies such as radiation or chemotherapy. However, since Pat’s doctors are choosing to be cautious with their surgical approach and remove less tissue than they would like to, they are recommending that she supplement this treatment with chemotherapy drugs. The most common chemotherapy regimen used by mesothelioma patients is a combination of pemexetred disodium and cisplatin, both of which are administered intravenously by a doctor every 3 to 4 weeks. Pemexetred inhibits the enzyme thymidylate synthase, which catalyzes the methylation of dUMP to dTMP, a precursor crucial for DNA synthesis. Cisplatin forms reactive platinum complexes that bind to GC-rich sites in DNA and create inter-strand crosslinks that prevent DNA helicases from properly unwinding the strands. Both of these drugs therefore act to prevent DNA replication, leading to the inhibition of cellular proliferation and initiation of apoptosis.

Unfortunately, chemotherapy drugs induce cell death non-specifically and kill many healthy cells along with cancer cells they are meant to destroy, so they tend to have side effects such as fatigue, loss of appetite, and anemia. Cisplatin in particular can cause kidney damage and worsen existing cases of kidney failure, but since Pat’s kidneys are healthy her doctors believe she will be unaffected. Recent studies have shown that the use of these chemotherapy drugs as adjuvant therapies along with surgery can significantly prolong patient survival, increasing median survival time from 20 to 30 months. Adjuvant radiation has also been proven to improve symptoms in mesothelioma patients along with chemotherapy and surgery, but it carries the added risk of introducing further mutations to cancer cells with dangerously high levels of genomic instability. For this reason, and because radiation can often worsen the symptoms of side effects produced by chemotherapy, Pat’s doctors decide not to treat her cancer with radiation therapy at this point.

In addition to the standard treatment methods, there are also many experimental treatments being explored, several of which show great promise for treating mesothelioma. The easiest of these to incorporate into existing treatment regimens is the combination of hyperthermia with chemotherapy. Recent studies have suggested that the elevation of body temperature during the administration of certain chemotherapy drugs can increase their efficacy, because the heat damages cancer cells without causing significant harm to normal tissue. A growing area of study for treatment of many cancers, including mesothelioma, is immunotherapy, which can involve stimulating a patient’s entire immune system to help it fight off the cancer, or directly supplying the patient with antibodies that recognize the specific type of cancer cells. The FDA recently approved such a monoclonal antibody for mesothelioma, the trade name of which is Avastin, that is usually used in combination with chemotherapy. This antibody specifically recognizes and binds markers on mesothelioma cells and targets them for destruction by the patient’s immune system, utilizing the body’s natural protection mechanisms to eradicate the cancer. Many of these experimental treatments are expensive and not covered by Pat’s insurance, but since whole-body hyperthermia can be induced by simply using heating blankets, her doctors decide to try it along with her chemotherapy treatment.