Squamous Cell Carcinoma Case Study

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September 21, 2016September 21, 2016Brian Mark SztoBIOL308 Team 3WSU Brian Mark SztoBIOL308 Team 3WSU Cell biology case studySquamous Cell CarcinomaCell biology case studySquamous Cell Carcinoma

September 21, 2016
September 21, 2016
Brian Mark Szto
BIOL308 Team 3
WSU
Brian Mark Szto
BIOL308 Team 3
WSU
Cell biology case study
Squamous Cell Carcinoma
Cell biology case study
Squamous Cell Carcinoma
Cell biology case study
Introduction
The patient is a 57-year old Caucasian male. He was born and lived in Greenbush, Minnesota, and has worked as a Corn/Soybean farmer for most of his life. From what we know, the patient is physically active, and is otherwise good. The patient's medical records state that he has had a tonsillectomy at the age of 6. He is also an active smoker.
The prognosis for the patient is Stage 2 squamous cell carcinoma concentrated in the superior lobe of the left lung, and on the superior and inferior lobes of the right lung. Genetic tests were done, and the results show positive for mutations in the EGFR and P53.
Summary of Treatment Options
There are several treatment options that lung cancer patients can take, but we have focused our research on Non-Small Cell Lung Cancer (NSCLC)1. These are the options:
Surgery- This option should only be used for an early stage of NSCLC, as it does not help with more advanced stages that have spread throughout the body. There are several types of surgery, such as: a Pneumonectomy which removes an entire lung, a Lobectomy which removes the tumor(s) containing lobe, a Segmentectomy where only a part of a lobe is removed, a Sleeve Resection which is used to treat some cancers in the large airways in the lungs and is an alternative to having a pneumonectomy in order to preserve more lung function, and Video-Assisted Thoracic Surgery(VATS) which is similar to a thoracic surgery but have been proven to be slightly better.2-4
This option is regarded as the best chance to cure NSCLC, as it involves physically removing the tumor(s), but it should only be considered if the tumor(s) can be removed completely.
The risks include pneumonia, excess bleeding, blood clots, and death.5
Radiofrequency (RFA)- This treatment method uses high energy radio waves to heat the tumor and destroy it. This option is usually for tumors that are near the outer edge of the lungs, and is good for patients who cannot tolerate surgery.6 The risks are uncommon, but include a partial collapse of a lung which leads bleeding into the lung.7
Radiation Therapy- This option has 2 types: External Beam Radiation Therapy that focuses radiation from outside the body into the tumor, and Brachytherapy that is used internally to shrink tumors in airways to relieve symptoms. This option is usually chosen if the tumor cannot be removed due to size or location, or if the patient is not healthy enough for surgery. It can also be used before surgery to shrink the tumor to make it easier to operate on, and after surgery to kill any remaining cancer cells. Radiotherapy can also be used together with chemotherapy.8 The risks include fatigue, nausea, vomiting, loss of appetite, weight and hair loss, as well as skin changes in treatment area.8
Chemo Therapy- This treatment method involves the use of anti-cancer drugs that are injected into a vein or taken by mouth. For NSCLC, usually 2 types of chemo drugs are used together. It can be used before surgery to shrink the tumor, or after surgery to kill remaining cancer cells. It is used as a main treatment for more advanced cancers, as it is able to affect the cancer cells throughout the body.10 The risks are similar to the risks of Radiotherapy.
Targeted Therapies- This therapy includes the usage of drugs that target certain parts of cancer cells that distinguish them from normal cells. Some ways that these drugs work are by blocking chemical signals that cancer cells depend on, triggering the body's immune system to kill the cancer cells, carrying a toxin to the cancer cell to kill it, but not normal cells, and more.10 The risks include low white blood cell count, lung inflammation, liver damage, and heart rhythm problems.
Immunotherapy- This method uses medicines to stimulate the body's immune system to recognize and destroy cancer cells more effectively. This can be used against certain types of NSCLC where a relapse happens.11 The risks are the same as the risks of Radiotherapy.
Promising chemotherapeutic drugs & mode of action
Chemotherapy is a widely used method to treat against more advanced cancers, but there are a few that are more specific for NSCLC. The drugs that we list here are ones that we think are suitable for the patient. 2 types of drugs are usually used together for NSCLC cases, but the ones listed below are ones that are more common, and could be used with other drugs to produce different synergistic effects. These drugs target the patient's mutations in EGFR.
Erlotinib(Tarceva) is a Tyrosine Kinase Inhibitor(TKI) that blocks the function of the EGFR on the surface of cancer cells that allow them to proliferate indefinitely. It works by inhibiting the EGFR's function to transmit received signals that cause a chemical reaction to modify other proteins.12 The drug targets the tyrosine kinase domain that does just that, hence its name. Erlotinib when used with Evofosfamide provides results in a combined ability to control the tumor's evolution and growth.13 Another combination of Erlotinib and Focal Adhesion Kinase(FAK) inhibitors has been proven to be effective in inhibiting EGFR TKI-resistant NSCLC cell viability and tumor growth.14
Gefitinib(Iressa) is another TKI that works in a similar fashion to Erlotinib, though the way it carries out its function may be different. Gefitinib competes with the binding of ATP to the TK domain of EGFR, which inhibits the receptor autophosphorylation that results in the inhibition on signal transduction. It may also induce cell cycle arrest and inhibit angiogenesis.15 Research has shown that Gefitinib is very effective against brain metastasis in lung cancer with EGFR mutation.16
Dichloroacetate(DCA) is a promising experimental drug that blocks key enzymes involved in glycolysis. In the 1920s, Nobel-prize winning German scientist Otto Warburg noticed that cancer cells produce the energy that they need via glycolysis, this is called the Warburg Effect. DCA works by targeting glycolysis-crucial enzymes in order to cut off the metabolism of cancer cells which leads to their death.17 A research has shown that Dichloroacetate effectively sensitizes most endometrial cancer cell lines to apoptosis.18
According to a research done by Yang Z and Tam KY, DCA when used together with EGFR TKIs such as those mentioned above, produces synergistic effects in combating NSCLC.19
Cellular abnormalities & efforts toward targeted drug therapies
The abnormal thing about cancer cell signaling is that they are able to create their own signals to survive without having to depend on any external signals. The kinases that are overexpressed are the growth promoting proteins such as EGFR and KRAS, which allow the cancer cell to proliferate indefinitely, while the tumor suppressor genes such as P53 are inhibited, which allows cancer cells to avoid apoptosis.
Since our patient has acquired EGFR and p53 gene mutations, we feel that it is important to include more information about them.
EGFR encodes a transmembrane tyrosine kinase with an extracellular ligand-binding domain and an intracellular component including a tyrosine kinase domain. Since EGFR is involved in regulation of numerous oncogenic functions such as cell proliferation, survival, differentiation, invasion and metastasis, activating mutations in EGFR lead to constitutive tyrosine kinase activation. 20-21
P53 gene acts as a tumor suppressor by regulating cell division and preventing them from growing or dividing too fast in an uncontrolled manner. Carcinogenic stress induces p53 leading to cell cycle arrest by inducing expression of cyclin dependent kinase inhibitors to undergo DNA repair or apoptosis. p53 inactivation is one of the most significant genetic abnormalities in lung cancer, occurring in 90% of Small Cell Carcinoma, and about 65% of NSCLC.20-21 In NSCLC, p53 mutations are associated with a positive smoking history or exposure to environmental tobacco smoke. Research has also shown that p53 gene mutations can occur in association with EGFR and KRAS mutations,20 which is like what our patient has been afflicted with.
These are some of the targeted drugs against EGFR oncogene and p53 gene22:
EGFR- AEE 788, AV-412, BMS-599626, BMS-690514, Canertinib, Cetuximab, CUDC-101EKB-569, Erlotinib, Gefitinib, Icotinib, Lapatinib, Matuzumab, Neratinib, Nimotuzumab, Panitumumab, Pelitinib, Vandetanib, XL647, Zalutumumab
p53- p53 peptide vaccine, PRIMA-1
Ongoing Clinical Trials
There are currently about 108 clinical trials new patients with NSCLC can enroll in. A clinical trial that is currently recruiting is done by the Barbara Ann Karmanos Cancer Institute focuses on treating NSCLC patients with Radiation Therapy, Chemotherapy, and Soy Isoflavones.23 Another trial conducted by the National Cancer Institute involves the treatment of T Cell Receptor Immunotherapy for NSCLC patients.24
Recommended Treatment Paradigm
The treatment that I recommend for Uncle Rudy to take is a combination of targeted and radiation therapy. Targeted therapy is needed because he has EGFR and p53 mutations that must be dealt with in order inhibit further growth of the cancer that might spread to the rest of his body, and radiation therapy is required to effectively destroy the cancer cells that are still localized in the lungs. Research has also shown preclinical evidences that targeted therapy agents can act as radiosensitizers and may improve cure rates when used in combination with Radiation Therapy.
As Uncle Rudy is a farmer, his general income may not be that high, but if finance were not an issue, I would also recommend that he take chemotherapy as well, in order to thoroughly rid the body of any remaining cancer cells should there be any. Although the side effects of these treatments may be great, it still does not outweigh the cost of allowing the cancer cells to live.



References
Non-Small Cell Lung Cancer Treatment. (2016, July 8). Retrieved September 18, 2016, from https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq#section/_164
Fan, J., Yao, J., Chang, Z., & Wang, Q. (2016, August 8). Left upper lobectomy and systematic lymph nodes dissection in enlarged pulmonary hilar lymph nodes in primary lung cancer patient by uniportal video-assisted thoracic surgery. Retrieved September 18, 2016, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999775/
Treasure, T. (2016, August 8). Videothoracoscopic resection for lung cancer: Moving towards a "standard of care". Retrieved September 18, 2016, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999685/
Feng, M., Lin, M., Shen, Y., & Wang, H. (2016, August 8). Uniportal video-assisted thoracic surgery for left upper lobe: Single-direction lobectomy with systematic lymphadenectomy. Retrieved September 18, 2016, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999655/
Baltayiannis, N., Chandrinos, M., Anagnostopoulos, D., Zarogoulidis, P., Tsakiridis, K., Mpakas, A., . . . Zarogoulidis, K. (2013). Lung cancer surgery: An up to date. Retrieved September 18, 2016, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791495/
Bargellini, I., Bozzi, E., Cioni, R., Parentini, B., & Bartolozzi, C. (2011). Radiofrequency ablation of lung tumours. Retrieved September 18, 2016, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259330/
Okuma, T., Matsuoka, T., Yamamoto, A., Oyama, Y., Toyoshima, M., Nakamura, K., & Inoue, Y. (2008). Frequency and risk factors of various complications after computed tomography-guided radiofrequency ablation of lung tumors. Retrieved September 18, 2016, from http://www.ncbi.nlm.nih.gov/pubmed/17985181
Radiation therapy for non-small cell lung cancer. (2016, May 16). Retrieved September 18, 2016, from http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-treating-radiation-therapy
Chemotherapy. (2015, April 29). Retrieved September 18, 2016, from https://www.cancer.gov/about-cancer/treatment/types/chemotherapy
Targeted therapy drugs for non-small cell lung cancer. (2016, May 16). Retrieved September 18, 2016, from http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-treating-targeted-therapies
Mountzios, G., Linardou, H., & Kosmidis, P. (2016, July 4). Immunotherapy in non-small cell lung cancer: The clinical impact of immune response and targeting. Retrieved September 18, 2016, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971380/
FDA Approval for Erlotinib Hydrochloride. (2013, July 3). Retrieved September 18, 2016, from https://www.cancer.gov/about-cancer/treatment/drugs/fda-erlotinib-hydrochloride
Lindsay, D., Garvey, C. M., Mumenthaler, S. M., & Foo, J. (2016, August 25). Leveraging Hypoxia-Activated Prodrugs to Prevent Drug Resistance in Solid Tumors. Retrieved Sept. 17, 2016, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999195/
Howe, G. A., Xiao, B., Zhao, H., Al-Zahrani, K. N., Hasim, M. S., Villeneuve, J., . . . Addison, C. L. (2016, March 10). Focal Adhesion Kinase Inhibitors in Combination with Erlotinib Demonstrate Enhanced Anti-Tumor Activity in Non-Small Cell Lung Cancer. Retrieved Sept 17, 2016, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786279/
Birnbaum, A., & Ready, N. (2005). Gefitinib therapy for non-small cell lung cancer. Retrieved September 18, 2016, from http://www.ncbi.nlm.nih.gov/pubmed/15610717
Chonan, M., Narita, N., & Tominaga, T. (2016, January 2). Total regression of brain metastases in non-small cell lung cancer patients harboring EGFR mutations treated with gefitinib without radiotherapy: Two case reports. Retrieved September 17, 2016, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698324/
Arney, K. (2010, May 12). Potential cancer drug DCA tested in early trials. Retrieved September 18, 2016, from http://scienceblog.cancerresearchuk.org/2010/05/12/potential-cancer-drug-dca-tested-in-early-trials/
Wong, J. Y., Huggins, G. S., Debidda, M., Munshi, N. C., & Vivo, I. D. (2008, April 18). Dichloroacetate Induces Apoptosis in Endometrial Cancer Cells. Retrieved September 17, 2016, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735772/
Yang, Z., & Tam, K. (2016, August 8). Result Filters. Retrieved September 18, 2016, from http://www.ncbi.nlm.nih.gov/pubmed/?term=Anti-cancer synergy of dichloroacetate and EGFR tyrosine kinase inhibitors in NSCLC cell lines
Cooper, W. A., Lam, D. C., O'Toole, S. A., & Minna, J. D. (2013). Molecular biology of lung cancer. Retrieved September 18, 2016, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804875/
Larsen, J. E., & Minna, J. D. (2011). Molecular Biology of Lung Cancer: Clinical Implications. Retrieved September 18, 2016, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367865/
Larsen, J. E., & Minna, J. D. (2011). Molecular Biology of Lung Cancer: Clinical Implications. Retrieved September 18, 2016, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367865/table/T3/
Gadgeel, S. M. (2016, February 8). Radiation Therapy, Chemotherapy, and Soy Isoflavones in Treating Patients With Stage IIIA-IIIB Non-Small Cell Lung Cancer. Retrieved September 20, 2016, from https://clinicaltrials.gov/ct2/show/record/NCT01958372?term=squamous non-small cell lung cancer
N. (2016, August 31). T Cell Receptor Immunotherapy for Patients With Metastatic Non-Small Cell Lung Cancer. Retrieved September 20, 2016, from https://clinicaltrials.gov/ct2/show/record/NCT02133196?term=squamous non small cell lung cancer















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