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I also researched some ways in targeting KRAS mutations. From the article titled, “‘Unexpected’ Vulnerability Creates Treatment Opportunity in Aggressive Type of Lung Cancer,” there has been studies done where XPO1 was used as an inhibitor. Since it was discovered that KRAS mutations rely on the protein, XPO1. Overall, it states that an XPO1 inhibitor would lead to a decrease in size of the tumor in NSCLC with KRAS mutations. Blocking XPO1’s activity lead to a disruption of the signaling pathway controlled by NFκB. NFκB is known to affects the activities genes involved in stimulating cell survival.

So far throughout our project we have discussed about using a protective coating around the drug. This protective coat will be made of a detergent containing a pH of 5.5. Detergents are able to disrupt membranes due to the amphipathic nature of both cellular membranes and detergent molecules. This means that they possess the characteristics of having both hydrophilic and hydrophobic regions. Detergent molecules are able to pull apart membranes. Some aspects I don’t fully understand yet are how we will be targeting and delivery our drug in a way that won’t affect other systems or pathways in our bodies. I still have to research ways in which drugs can be delivered in a way that they target the pulmonary vein. One way we could assay our treatments is by monitoring whether the tumor has spread through scans if we were working on real patients.  We would have to perform tumor genomic assays. At the molecular level we would have to be monitor the overexpression of AATF. But also, other types of cells to see if our drug could have programmed cell death in places where it shouldn’t have. 

Malignant transformation depends on robust mechanisms to override DNA damage response signaling to preserve their proliferation speed despite the genotoxic abrasions.  According to the article, “AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer,” tumor cells rely on the effective suppression of p53-mediated induction of apoptosis regardless of their genomic instability either through TP53-inactivating mutations or through counteracting signaling molecules. In addition, it has also been known that lower levels of AATF protein expression correlate with higher expression rates of p53, Puma, and cleaved Caspase-3. This is all after genotoxic stress. AATF is also referred to as Che-1 and from “The anti-apoptotic factor Che-1/AATF links transcriptional regulation, cell cycle control, and DNA damage response,” article it states, that its phosphorylated by ATM and Chk2 and this leads to the stabilization of AAATF. As a result, it increases p53 and p21 expression contributing to stopping cell growth in response to DNA damage.

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Figure 1. Canis lupus familiaris skull (Dog skull)

Depicted in the image is a labeled skull of a Canis lupus familiaris. It clearly illustrates the carnassial complex. The carnassial complex is a specialized sectorial (cutting) teeth. The upper and lower jaw contain incisors, canine, premolars and molars. In the upper jaw it shows the last upper premolar versus the lower jaw which shows the first lower molar.

For centuries, we have studied cancer and the affects it bestows upon the human body. Today, we try a variety of methods to tackle cancer and beat it. For our project, we decided to focus our attention on lung cancer. In specifically, non-small cell lung cancer. According to the American Cancer Society about 80%-85% suffer from non-small cell lung cancer. Squamous cell carcinoma, adenocarcinoma, and large cell carcinoma are subtypes of non-small cell lung cancer (NSCLC). We will be focusing on KRAS and its association with lung adenocarcinoma. In addition, we will also be discussing Keap1 and AATF. One challenge will be facing during our research, is in delivering a treatment that would only target the cancer cells. One idea we are looking into at this moment is to create a drug that will be delivered intravenous. We will be targeting the lungs via the pulmonary vein. Non-small cell lung cancer is a type of cancer which we will be able to build off since it is also known to be metastatic. 

According to the article titled, “Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis,” “Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1, a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response.” This article essentially states that we should look at a glutaminase inhibition approach. After doing some research, I have learned that if we were to remove glutamine from the body then this would mean a reduction in cell growth or prompt cell death. But what if we remove it and it leads to increase in cell death where there shouldn’t be. I remember from lecture it being mention how in some patients they affected red blood cells and then led to high risk patients with anemia. I am having a hard time wrapping my mind in figuring ways where we won’t be affecting other functions and cells. In my research it also mentions how this indicates that these cells are dependent on, or “addicted” to, glutamine. 

The KRAS gene provides instructions for making a protein called K-Ras. It’s part of a signaling pathway known as the RAS/MAPK pathway. In RAS/MAPK we know that an activated RAS activates MAKKK by binding to it. Then activates MAPKK by phosphorylation and then MAPK. Then MAPK activates proteins or transcription regulators in order to either change protein activity or alter gene expression. The protein relays signals which instruct the cell to grow, divide, and differentiate. The K-Ras protein is a GTPase. When the protein is bound to GDP, it does not relay signals to the cell's nucleus and when its bound GTP it does. The KRAS gene belongs to the oncogene class. From lecture we have learned that when mutated, oncogenes have the potential to cause normal cells to become cancerous. 

Figure 10.8 (A) and (B) illustrated a huge decline before rising back up and then flattening out. Where lambda is eventually beginning to settle to a constant value although we still see smaller increases and decreases throughout the years. Some of the reasons these differences could have occurred could be the difference in the number of newborns present. In addition, we only show data for up to 5 years versus 11 years and we had the low number of three-year olds compared to the graph 10.8. Where we could see the oldest generation had the most abundant members and the newborns had the least.  As we have learned during lecture, if reproduction rates and age-specific survival rates have no change, then the population growth rate will eventually be stable. Based on the graph and what we have learned, in the future years we will see population stabilizing and stay the same that is if the age specific survival rate has no change. 

AATF also referred to as, Apoptosis Antagonizing Transcription Factor, is a regulator of p53 in DNA damage response. It is known to inhibit apoptosis in vivo and be overexpressed in lung cancer. In Kras-driven lung adenocarcinoma if the deletion of AATF occurs then this results in delayed lung cancer formation mainly in a p53 dependent manner. Targeting AATF will be targeting tumor progression and putting a stop to it. AATF through the PI3K/Akt pathway can inhibit Ba. This then results in the activation of BCL-2 leading to immortality of these multiplying cells.  We know that BCL-2 works in the survival pathway. Its job is to stop cell death. When a phosphate is added to Bad it could then prevent it from sequestering Bcl₂, so Bcl₂ can do its function. Bad prevents Bcl₂ from doing its job. When Bad is bound to Bcl₂, the cell will die, however, when Bad is not bound to Bcl₂, Bcl₂ will be active and it will stop cell death. In order to keep Bad inactive, protein 14-3-3 will make sure a phosphate is stuck on Bad. 

Cancer is most commonly referred to as a state in which there is uncontrollable cell division. In today’s society, we try to tackle the pathways that are affected by a variety of cancers. For our project, we decided to choose lung cancer and in specifically, non-small cell lung cancer. According to the American Cancer Society about 80%-85% suffer from non-small cell lung cancer. It is very common and can be subdivided into Squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. We are focusing on Kras and its association with lung adenocarcinoma. We will also be discussing Keap1 and AATF. This type of cancer is known to be widespread and lethal. Our challenge will be in delivering a treatment that would only target the cancer cells. An idea we are looking at in this moment is to have a drug that will be delivered intravenous so that we may target the lungs via the pulmonary vein. Non-small cell lung cancer also referred to as NSCLC is a cancer which will be able to build off since it is also known to be metastatic.