Saturday, May 31, 2014

Crohn's Disease as a potential risk factor for Gastrointestinal Cancer development

At the age of ten, I was diagnosed with a Gastrointestinal condition known as Crohn's Disease. While this introduced several complications such as immune system compromise, severe abdominal pain, and difficulty with weight gain, I have since brought my condition under control, I am for all intents and purposes healthy and stable! Having a condition, however, pushes you to the brink of curiosity. Though I have learned a lot about Crohn's since being diagnosed, I have always wondered if a correlation exists between development of this disease and cancer risk. To my surprise, I stumbled upon a study conducted in Denmark looking specifically at patients with Crohn's disease and the resulting risk of cancer development.

A closer look into CYP7B1

As our project progresses, Matt and I are starting to delve deeper into many of the topics associated with cholesterol and cancer.  One of these very important topics is 7ɑ-hydroxylase (usually referred to by its gene name CYP7B1), a very important enzyme that works to hydrolyze the infamous 27-hydroxycholesterol (27HC).  27HC is a cholesterol metabolite that has recently been shown to promote ER positive breast cancer.  This is really all you need to know about this molecule.  However, for more information on 27HC, you can search the blog for my earlier post Cholesterol and its Promotion of ER+ Breast Cancer.  If you are unable to find my post, follow this link to another information page for 27HC.

Oral Contraceptives effect on Breast and Ovarian Cancer Risk

       In Megan and Christina's presentation, they discussed how the increased level of estrogen and progesterone during pregnancy causes breast tissue to differentiate and ultimately decreases risk of developing breast cancer. Because most combination birth control pills contain both estrogen and progesterone it made me curious about if the use of oral contraceptives can have similar effects of pregnancy and decrease risk of breast cancer. However, the information I found was opposite of what I had anticipated.

Friday, May 30, 2014

Tumor Suppressor Functions and Mutations of NOTCH1 in HNSCC

Figure 1. Duality of Notch functions in keratinocyte commitment to differentiation and cell survival. Notch signaling impacts on, and is regulated by a complex signaling network with an important role in skin homeostasis and tumor development. Like Notch, many other components of this network exert a duality of functions, impinging on keratinocyte growth/differentiation control as well as cell survival. This has potentially important implications for cancer therapy. An attractive approach could be the use of selective inhibitors, which can suppress the Notch prosurvival function while leaving intact or enhancing its ability to induce differentia- tion. Alternatively, Notch inhibitors, or inducers, could be used as part of a combination therapy in conjunction with other compounds with growth inhibitory and/or pro-apoptotic functions. 

KRAS Mutations and Acquired Resistance to Cetuximab

Throughout my blog posts, I have been looking closely at a paper whose authors claim that KRAS mutations cause acquired resistance to an anti-EGFR therapy drug called cetuximab for colorectal cancers. My last blog post examined the data of one of the cellular models, DiFi, and now I will do the same for the other, Lim1215. These cellular models are used to help define the molecular basis of this secondary resistance, which in the future can help prevent such matters. Lim1215 cells express normal levels of EGFR, while DiFi overexpressed EGFR, but both are similarly sensitive to cetuximab.

Thursday, May 29, 2014

Autocrine Motility Factor

Our project’s topic illustrates how AMF induces phosphorylation of the HER2 receptor and thus activates its signaling pathway. HER2 breast cancer is when the breast cancer cells have an amplification of HER2 2 receptors on the surface of the cell. With this increased number of receptors cell proliferation is increased resulting in cancer. HER2 breast cancer is often treated with the Trastuzumab(Herceptin) drug. This drug works by first attaching onto the HER2 receptor on the extracellular side, which then stops the receptors from signaling downstream. Many patients who take Herceptin become resistant to its effects. My group will explore the theory that the interaction between AMF and HER2 causes the resistance to the drug. AMF’s phosphorylation of HER2 activates phosphoinositide-3-kinase and mitogen-activated protein kinase signaling. This happens regardless of Herceptin involvement. This is important because the AMF-HER 2 interaction may be a viable target for therapeutic treatment of patients with breast cancer.

Beyond Standard Therapies in Metastatic Colorectal Cancer

After all standard therapies for treating metastatic colorectal cancer are exhausted, there are no interventions to improve the quality or length of life of the patient. However, patients with cancer that progresses despite therapy are possible candidates for further intervention. One therapy that can be used is multikinase inhibitors. They block intracellular and cell surface kinases, some of which are involved in tumor growth and the metastatic progression of cancer. These multikinase inhibitor drugs can reduce cell replication and tumor growth and are used to treat cancer in advanced stages. For metastatic colorectal cancer, a phase 3 trial was done internationally for the multikinase inhibitor Regorafenib.

Notch1 Helps or Hinders Tumor Formation in Conjunction with HPV?

In HPV positive cervix cancer, one cannot develop cancer solely from having HPV; additional mutations, such as NOTCH1 mutations, are necessary to instigate tumorigenesis. Different studies have yielded contradictory results of whether Notch1 acts as either a tumor suppressor protein or an oncoprotein in HPV positive cervical cancer. In this article1, the authors observed that when Notch1 is expressed excessively, it acts as a tumor suppressor in HPV positive cervical cancer; however, when it is expressed in moderate amounts in conjugation with constitutively active PI3K, it presented oncogenic properties.

Wednesday, May 28, 2014

Sunscreen and p53: A Case Study

In my recent blog post, I discussed the p53 gene, and experiments testing sunscreens effect on p53 in mice. In this blog post, I will discuss a study testing sunscreen’s relation to p53 protein production done on humans. From 1992-1996, the NambourSkin Cancer Prevention Trial conducted a study to test the association of time spent outdoors and the expression of p53, as well as its relation to the use of sunscreen. Researchers predicted that sunscreen counteracts p53 production, and carried out their research on over 160 random participants for 6 months. There were four different treatment groups: 1. Application of SPF 16 sunscreen daily + beta-carotene supplementation, 2. Application of SPF 16 sunscreen daily + placebo tablets, 3. Beta-carotene only, 4. Placebo only. Beta-carotene is a type of pigment called a carotenoid, and produces Vitamin A, which helps prevent cell damage. It’s thought to be possibly effective for people who are sensitive to sun exposure in order to help prevent sunburn, but the exact efficiency is not known.

The CRISPR/Cas9 genome editor and its therapeutic potential

In the first few weeks of the quarter we had a lengthy discussion on the origins of cancer cells. Loss of function mutations in tumor suppressor genes and gain of function mutations in oncogenes lead to the deregulation of the cell cycle and eventually uncontrolled cell proliferation. Gene therapy has been considered as an option to rehabilitate these genes back to a functional state. Unfortunately, the methods researched in the last three decades since the principle discovery of gene therapy, such as retroviral vectors, have been incredibly inefficient and have a low ceiling due to inherent low indel (nucleotide insertions or deletions) specificity. Within the last fifteen years though, three restriction enzymes (used to cut DNA at relatively specific sites) have been heavily researched in hopes of finding a mechanism to make the ultramodern form of gene therapy a reality.

Tuesday, May 27, 2014

Reactivated Telomerase and Prostate Cancer in Mice

In order to determine the role of telomerase in prostate cancer, researchers used a mouse model that was null for Pten and p53, meaning that these tumor suppressor genes lacked proper function and couldn't produce viable proteins.

Monday, May 26, 2014

Beer: As a Risk To Your Health or as Cancer Prevention

Barbeque on a sunny afternoon is one of the most common activities of many average Americans. The charred, heated part of meat on the grill are the pieces that many of us like most about our meat, but evidence has been shown that these are made up of carcinogenic substances.

A negative side effect of BRAF targeted drug therapy with a promising future

In my last blog post I wrote about a new promising drug called dabrafenib, but some negatives about this drug included resistance and side effects.  In order to address the issue of resistance, a drug that targets a different part of the MAPK signaling pathway called trametinib is used in drug combination therapy.  In chemotherapy using just dabrafenib there was a response rate of 56% and in combination therapy there was a recorded response rate of 76%.  Dabrafenib targets the BRAF protein while trametinib targets the MEK protein, which can be seen in Figure 1.

Sunday, May 25, 2014

YOU Can Kill Your Own Cancer! Immunotherapy and Metastasis

     A new method of immunotherapy developed by researchers at the National Cancer Institute has proven successful in the reduction of a metastasized tumor size by specifically attacking tumor cells that have mutations unique to a patient's cancer. The researchers demonstrated that the human immune system can mount a response against mutant proteins expressed by many common cancers that arise in epithelial cells which can line the internal and external surfaces of the body. 

KRAS Amplification and Acquired Resistance to Cetuximab

In my last blog post, I examined questionable factors of a paper whose authors conclude that KRAS mutations drive acquired resistance to an anti-EGFR therapy drug called cetuximab for colorectal cancers. My main concern is with the strength of the authors’ conclusion and if the data is sufficient enough to lead to a causal relationship. This paper presents two main overall sets of data. The first is in regards to the molecular mechanisms of secondary resistance to anti-EGFR therapies, while the second set attempts to determine clinically if KRAS mutations or amplifications are related to acquired cetuximab resistance. For this blog post, I will examine one part of the first data set.

Measles Virus Provides New Hope for Development of Cancer Vaccine

In lecture we learned about the use of vaccines as a preventative measure for cancer, but what if a vaccine could be used to cure cancer? Results from a recent phase 1 trial suggest that this may be a real possibility. After intravenously injecting myeloma patients with the MV-NIS, a genetically engineered measles virus, researchers observed them reach a state of complete remission.

Saturday, May 24, 2014

Sunscreen and Skin Cancer: Avobenzone Optimization

To conclude the Sunscreen & Skin Cancer blog series, I am going to tie up some loose strings by discussing the role of the avobenzone sunscreen active in commercial formulations and methods used in order to optimize its ability to attenuate UVR.

Dental X-rays and Thyroid Cancer

In my first blog, I talked about the increased risk of thyroid cancer from childhood therapeutic radiation. This therapeutic radiation was used for acne treatment, lymphoma, Hodgkin’s, and tonsil cancers. I mentioned however that since the 1950’s, therapeutic radiation has only been used in children in cases of morbidity and mortality. But if these therapeutic radiations have decreased, why is the incidence increasing?

Friday, May 23, 2014

Hypomethylating Agents in AML Treatment

A major determinant of chemotherapeutic treatment is whether a patient’s risks of severe side effects would outweigh their benefit from the therapy. In this post, I will look into how the effectiveness of hypomethylating agents in Acute Myeloid Leukemia compares to their promise, especially in older patients who have lower rates of survival and are more susceptible to side effects of treatment. Often these patients do not receive any form of intensive treatment, since the toxicity is not worth the cancerous cell death. The standard AML treatment of high doses of cytarabine, an antimetabolite which inhibits DNA synthesis during the S phase of mitosis, also damages healthy cells with its high toxicity. The American Cancer Society reports the average AML patient age as 66 years old, so the majority of patients with this type of leukemia would not be ideal recipients of the standard-of-care treatment (1).

Wednesday, May 21, 2014

New Prostate Cancer Screenig Method

This research article focused on variances in the levels of different microRNAs (miRNAs) in both the blood and urine of patients with prostate cancer, some of which were metastatic. First off, it is necessary to understand what miRNAs are. They are very short, non-coding, sections of RNA that bind to complementary mRNAs and alter gene expression. So far, about 1,000 miRNAs have been discovered, and each of these is capable in altering the gene expression of up to 1,000 genes. The hypothesis of this research team was that differences in the levels of circulating miRNAs in blood and urine could be correlated to prostate cancer. Furthermore, they also believed that they could predict if the cancer was metastatic or not.

Are all Thyroid Cancers the same?

Throughout all the posts Analisa and I have been doing it has become apparent that when talking about thyroid cancer not all are the same.  There is Papillary carcinoma, Follicular carcinoma, and Sporadic and Familial Medullary Thyroid carcinoma, although some occur more often than others (the three being a rare form of thyroid cancer.) So why do we care?  Before I answer I will explain the differences in all of them as provided by the American Cancer Institute1.  

"An Apple a Day" No Longer

       We all know the age-old saying, "an apple a day keeps the doctor away." A 1997 report, Food, Nutrition, and the Prevention of Cancer: a Global Perspective by the World Cancer Research Fund and American Institute for Cancer Research, supported this adage, declaring "convincing" evidence that "diets containing substantial and varied amounts of vegetables and fruits will prevent 20 percent or more of cancers." For 10 years, this report existed as the most authoritative and influential source in the field. Since the publication, both interest research on the topic has grown rapidly. A second report in 2007, Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective, by the same foundations, reviewed all the relevant research concerning food, nutrition, and cancer prevention.

A new mechanism of Herceptin resistance?

For the Cancer Project, Michael Allen and I are studying HER2 breast cancer.  As we all know from class, trastuzumab, or Herceptin, is one of the monoclonal antibodies able to treat HER2 breast cancer. However, patients treated with Herceptin soon become resistant. As a result, elucidating mechanisms of Herceptin resistance is extremely important. The paper that we are focusing on proposes that a ligand, Autocrine Motility Factor (AMF), somehow induces HER2 phosphorylation and resistance to Herceptin.  This past summer, I actually was able to perform some of these experiments myself and determine whether or not these results were repeatable.

Relatively Indolent But Relentless

If you're interested in something a little different, check out a nice little article in the about Matt Freedman and his illustrated journal of life during cancer therapy. Relatively Indolent but Relentless was just published last month (Seven Stories Press) and appears to be an unvarnished account of what it's like to go through cancer (radiation) treatment.

Pragmatic Complementary Therapy for Breast Cancer

     In examining the complementary therapy of exercise for breast cancer patients I was struck by a pressing question concerning the pragmatism of this therapy in comparison to what is currently available. Especially, since the incidence of breast cancer is continuing to increase and in 2008 alone it affected 1 million women globally. It is worth considering exercise as a complementary therapy that may be a more cost effective means in providing treatment for breast cancer patients.

Tuesday, May 20, 2014

Analysis of CTC Concentration in Blood

As my partner had illustrated in his own blogpost, there is believed to be a negative correlation between CTC count and the severity of cancer. The study of CTCs is relatively new and there is a lack of general consensus on what dangerous levels of CTCs actually are. Therefore, most studies determine a concentration of CTCs in the blood at which the patients are believed to be at risk. This is accomplished through a series of tests in which the experimenters take a series of CTC concentrations that they believe to be relevant and note at which concentration the hazard ratio appears to significantly increase. A hazard ratio is a description of the relative risk of a complication occurring with or without a specific event. In CTC studies the event would refer to CTC concentration while the complication could be death or cancer progression. However, the identity of these variables is the choice of the researchers. Once a CTC concentration is determined to be related to a relevant change in hazard ratio, it is labeled as the cutoff value. This cutoff value is then used to mark the change between high and low CTC counts.

Sunitinib Malate as a Second-Line Therapy for Metastatic GIST

        The primary therapy for GIST is surgery, but for cases that are metastatic or unresectable, a tyrosine kinase inhibitor alone or in addition to surgery is the next option. Imatinib mesylate, or Gleevec, is usually the drug given to GIST patients, but as Shiona previously discussed, about 15% of patients with GIST exhibit primary resistance or intolerance to Imatinib. A therapy option available to these patients is Sunitinib malate(Sutent), a multi-targeted tyrosine kinase inhibitor.

Metformin: Decreasing mRNA Expression of Proteins Vital to Pancreatic Cancer

            For my final post I wanted to focus on the topic that our cancer project centers around: the use of the anti-diabetic drug metformin as a potential chemopreventative for pancreatic cancer. Many papers, including the paper I have chosen to analyze, focus on the link between pancreatic cancer (PC) and diabetes mellitus. It is because of this link that researchers believe the answer to decreasing the vast number of new cases of PC developing in the world is in a drug used to treat diabetes mellitus. Pancreatic cancer, with the most common type being pancreatic ductal adenocarcinoma (PDAC), is characterized by uncontrolled cell growth in the tissues of the pancreas (Ref. 1). According to various epidemiologic studies, there is an increased risk of developing PC associated with diabetes mellitus (Ref. 2). Diabetes mellitus is characterized by an abnormality in the body’s ability to either produce or use insulin efficiently, known as insulin resistance (Ref. 1). Both of these situations result in chronic hyperglycemia in the blood stream. PC is one of the deadliest forms of cancer with more than 38,460 deaths in a single year (of the 42,220 total new cases) (Ref. 2). There is a desperate need for a preventative drug or an effective treatment to inhibit the cell cycles in tumor cells or prevent the hyperactivation of certain pathways.

Fragment-Based Lead Discovery

After doing some browsing regarding my cancer project, I came across a chemotherapeutic drug used to treat late stage malignant melanoma called Vemurafenib.  This particular targeted drug therapy was found through fragment-based lead discovery.  I had no idea what this drug discovery method entailed.  Fragment-based lead discovery is a new approach developed this decade that is increasingly used in the pharmaceutical industry. 

Promising new drug dabrafenib has accelerated FDA approval for treatment of metastatic melanoma

In my last blog post I talked about how the project of genome sequencing led to the discovery that a mutation in the BRAF gene causes most metastatic melanomas.  This discovery was predicted to have a promising future in drug discovery that targeted this gene, which proved to be true.
            The most common mutation found in 80-90% of B-Raf mutant cancers is the B-RafV600E mutation.  This mutations substitutes valine with glutamic acid at amino acid 600, which mimics phosphorylation used to regulate growth activity.  The mutation leads to a 500-fold increase in activity of the protein compared to wild-type B-Raf, ultimately showing an oncogenic addiction in the MAPK signaling pathway.  This leads to tumor growth.

Sunday, May 18, 2014

Delving further into circulating tumor cell counting accuracy

In my last blog post, I gave a brief introduction and my own analysis of one study done with circulating tumor cell (CTC), emphasizing some of the topics that we covered earlier in this quarter. This week, I focused on a study described by another paper with particular focus on the variables that may render analysis of circulating tumor cells ineffective as a predictor for reactions experienced by cancer patients. There were also some inconsistencies that I noticed between this study and the one I analyzed in my last post and I will be addressing these differences later in this post.

Breastfeeding as a potential risk reduction factor for Breast Cancer

After spending a week discussing cancer prevention, I became incredibly interested in the role of lifestyle choice in cancer development. Though we discussed this briefly, our everyday nutrition, exercise, and routine choices are proving to play an integral role in our individual overall health, including decreasing our risk for developing cancer. And as one of the leading subsets of cancer incidence among women, breast carcinomas have become a highly researched and dissected cancer; in the year 2010 alone about 1.5 million people worldwide were diagnosed. Thus, more individuals have become concerned with lifestyle-oriented health, looking specifically at the modifiable factors in breast cancer prevention. 

Interactions between DNMT3A and other AML-related genes and treatment options

What other genes interact with DNMT3A that complicate the prognosis of AML?

Although in my previous posts, I have focused exclusively on the DNMT3A mutation and its mechanism in AML, clinical practitioners focus on multitude of other recurring genes and abnormalities that are overexpressed in AML patient genomes to aid in prognosis at initial diagnosis. Among such molecular markers are mutations in FLT3, NPM1 (which I have mentioned in my previous discussions of DNMT3A), and c-KIT. My goal is not to provide an exhaustive discussion about the involvement of these genes in the disease as they deserve entirely separate discussions of their own, but to provide a brief overview of them, as it turns out creating future therapies will need to target them as well. 

FLT3 is a receptor tyrosine kinase that spans the plasma membrane and has an important role in proliferation, survival and differentiation of hematopoietic progenitor cells. The incidence of this mutation in AML patients is about 25%, although this varies depending on age, clinical risk, and is more common in adult AML instead of pediatric AML and  myelodysplastic syndrome (MDS), which is a related malignancy that can give rise to AML. It was noted in this paper that several FLT3 inhibitors are currently in various stages of development.

The Biochemical Mechanism Behind Paradoxical Activation in BRAF Wild-type Cells by BRAFV600E inhibitors

In my last two blog posts I wrote about a unique case in cancer therapeutics where the successful treatment for a BRAFV600E metastatic melanoma with the vemurafenib BRAF inhibitor drug caused the development of chronic myelomoncytic leukemia in the same patient with a preexisting KRASG12D mutation.  It was shown through in vitro assays that the Map Kinase pathway was being turned on in KRAS mutant and BRAF wild-type cells causing uncontrollable cellular proliferation.

Friday, May 16, 2014

A Measles Vaccine Kills Cancer?

     They hook you up and then, five minutes into the hour-long process, you get a terrible headache. Two hours later, you start shaking and vomiting and your temperature hits 105 degrees. That doesn't sound like too much fun. But what if this was all you had to endure in order to get rid of your cancer?

Notch's Oncogene Role in T Cell Leukemia

Dual role of Notch signaling in cancer    

The table above originates from a review article titled, Oncogenic and Tumor suppressor functions ofNotch in cancer: It’s NOTCH what you think, which was published in The Journal of Experimental Medicine. This table is essentially the overall theme of our Cancer project showing how the role of the Notch signaling pathway can play both the role of an oncogene and the role of a tumor suppressor gene, depending on the type of cancer.3

Thursday, May 15, 2014

Cholesterol and its promotion of ER positive breast cancer

For our project, Matt Perez and I are looking into the effects that cholesterol has on ER positive breast cancer.  This article has made this connection, illustrating that increased levels of cholesterol can work to promote tumor growth and hurt the survivability of the patient.  However, it is not cholesterol itself that is the culprit.  It is a primary cholesterol metabolite (Figure 1) called 27-hydroxycholesterol (27HC) which works to promote estrogen receptor (ER) positive tumor growth.  The figure below illustrates the cholesterol metabolic process and the similarities between Estrogen and 27HC, both tumor promoters.  The fact that Estrogen and 27HC are both products of the cholesterol metabolic process provides some reasoning as to why 27HC shows ER agonist activity, that is the ability to bind to a estrogen receptor and mimic its activity, causing for the promotion of tumor growth.

Is There A Protective Role of Tea Against Cancer?

Everyone loves a nice warm cup of tea when they are sick or feeling worn out. Throughout the years tea has seemed to have a soothing effect on people and has become associated with making people recover faster from the cold or flu. But what if tea is way more important than that; what if tea could keep you from getting cancer!? According to Lambert and Chung, there is a component in green tea called catechins that may aid in many cancer preventive functions such as inhibiting growth factor signaling, promoting apoptosis, and inhibiting protein kinases from functioning. Catechins are defined as a polyphenol compound from the plant Camellia sinensis and have been thought to have antioxidant properties. I am aiming to analyze this claim and get a better idea about how much of a preventative effect tea really has.

Wednesday, May 14, 2014

Cancer Miracles--Surviving Certain Death through Spontaneous Tumor Regression

Imagine finding a small lump on your body one day that causes pain like nothing you’ve ever felt before. Imagine that upon discovering this lump and visiting the doctor, the physician confirms that you have cancer. What’s worse is that it is inoperable and doctors say there is nothing they can do. The doctor then says you have a month (or even less) to live. Now imagine this: one day, all the pain goes away and a resulting trip to the doctor reveals no sign of cancer, and there are no signs of cancer in the years to come. Sounds hard to believe, right?

Therapeutic Panitumumab-FOLFOX4 intervention with KRAS exon 2 mutation in colorectal cancer.

My partner Tien Lu and I are conducting our cancer project on how mutations in RAS can affect the of anti-epidermal growth factor receptor (EGRF) in colorectal cancer. EGRF is a cell-surface receptor that stimulates protein-tyrosine kinase activity when dimerized. EGRF can activate KRAS, and has been identified as an oncogene. Oncogenes can cause cells selected for apoptosis to survive and proliferate. A RAS mutation can be any KRAS or NRAS mutation in exon 2, 3, or 4. In some instances, it is possible that wildtype RAS allow for antibodies to target EGRF and reduce tumor size in colorectal cancer. Thus, there is the question on how patients with metastatic colorectal cancer with KRAS mutations in exon 2 that are given anti-epidermal growth factor therapy will fare compared to their wildtype counterparts. These mutations can then be used as predictive biomarkers to allow Doctor's to supply more individualized treatment to specific patients. In a clinical trial for the efficacy and safety of Panitumumab conducted by Dr. Douillard of ICO, patients were treated with FOLFOX4 and FOLFOX4 + Panitumumab. Panitumumab, compared to FOLFOX4, is more highly selective for EGRF.

Tuesday, May 13, 2014

Possible Therapy Targeting the NOTCH1 gene

    As our class has been studying the treatments of cancer and how drugs are developed in the clinical and pre-clincal settings, I have been interested in researching therapy targeted against NOTCH1. While I was doing this, I stumbled upon one article, Notch1 as a Potential Therapeutic Target in Cutaneous T-cell Lymphoma, that researched the possible therapeutic properties of inhibiting the Notch1 pathway (see blog 1 paragraph 2 for simple pathway) in cutaneous T-cell lymphoma.

KRAS Mutations Drive Acquired Resistance to Cetuximab in Colorectal Cancers?

          For the cancer project, Ramez Sakkab and I are taking a closer look at colorectal cancer (CRC) therapy. A popular type of therapy is anti-EGFR therapy, targeting the epidermal growth factor receptor (EGFR).  EGFR is a receptor tyrosine kinase that activates KRAS, which eventually leads to the expression of growth-promoting genes. EGFR also activates another pathway that results in protein synthesis, cell growth, survival, and proliferation. The inhibition of EGFR is beneficial for CRC patients, but after an initial response to therapy, some grow to be resistant. The paper that I am interested in investigates this resistance specifically to the drug cetuximab, which binds the extracellular domain of EGFR, preventing ligand binding and interrupting the signal cascade. The authors conclude that mutations of KRAS have a causal relationship with the acquired resistance to anti-EGFR treatment. For this first blog post, I will address my initial thoughts and impressions regarding this paper.

VSV Variants as the "Perfect" Oncolytic Virus?

This post is going to be a continuation from my previous post. I received some very insightful comments challenging me to look further into the use of virus particles and variants as means of ridding the body of cancerous cells. The idea that researchers have been injecting live virus variants into animals, in this case mice, and these variants have been successful at killing off tumor cells is encouraging to the world of cancer research (Ref. 4). However there are a few caveats that even the paper’s authors recognize and explore.

The p53 Gene

            The p53 tumor suppressor gene is responsible for producing the p53 protein, which works to repair the cell when DNA damage is detected. Some of its roles include arresting the cell cycle before replication, inducing apoptosis, or binding to promoter regions to prevent transcription of certain genes. There are about 100 proteins that p53 regulates, and the article I am going to discuss focuses on its relation to skin cancer and regulating UV-induced DNA damage. The article also looks at how p53 can serve as a biological endpoint to evaluate the efficacy of sunscreens in preventing UV-induced skin cancer.

Comparison of L3MBTL1,TP53, and KRAS

     Another means to evaluate the validity of L3MBTL1 gene as a tumor suppressor gene is to compare this gene to TP53 and KRAS. An inference regarding L3MBTL1 as a tumor suppressor may be made based on this comparison because tumor suppressor genes and oncogenes display distinct patterns of mutations. It is critical for Sonya and me to establish if L3MBTL1 is a tumor suppressor gene because this is one of the main assumptions of the study (Figure 2). TP53 is a known tumor suppressor and KRAS is a known proto-oncogene (Figure 1, 3). This comparison should illuminate whether L3MBTL1 is a tumor suppressor gene based upon what mutated gene type it resembles more. A histogram from Cosmic Database is provided below of the mutations in cancer. The data is based on examination of somatic mutations in cancer and on examination of select papers from PubMed.

Monday, May 12, 2014

DNMT3a mutations as predictors of poor outcome in AML

In my previous post, I introduced how the mutation of DNMT3a is frequent in differentiated hematopoietic stem cells in Acute Myeloid Leukemia. Before focusing on treatment, I wanted to first look further into why the DNMT3a mutation was a driver of AML progression.  Once a DNMT3a mutation is found in a patient, it signifies that the leukemia has progressed enough that the cancer will have a poor outcome.

Re-Visiting Cell Phones Heat and Cancer

Climate and Cancer

In my previous blog post, I discussed the connection between cancer and cell phones. It was brought to my attention (by Dr. Islas) that I could take this data one step further to determine how heat impacts cancer. Here is a review of my previous conclusions...

Oncolytic Viruses: the homing missiles of cancer therapy

...or evil.
I think viruses are cool. I mean, really cool. I listen to a weekly podcast on viruses when I’m in the shower, lab, car, or on a run and I keep up with a couple of virus blogs that talk about viral global health concerns and related research. I don’t really have a good reason for my viral fascination other than that they’re a cultural taboo. They’re portrayed in the general public as vectors of disease and death, but in reality viruses are so diverse, so versatile, and so omnipresent that their pathogenicity is incredibly variable. Viruses like smallpox and HIV can ravage a society, but some, like the set I will be taking about, can be used to fight a variety of cancers...

So without further ado, I am excited to present my first post on the fascinating world of Oncolytic (onco=“cancer” and lytic=“bursting”) Viruses.

Sunday, May 11, 2014

True Increase in Thyroid Cancer Incidence? Maybe not

Many data registries have shown an increasing trend in thyroid cancer incidence, however it is questionable as to whether the numbers are due to an actual increase in incidence or due to and increase in detection of pre-existing cancers because of an improvement and increase in cancer screening techniques. Dr. Louise Davies and Dr. H. Gilbert Welch have investigated the cause of this increasing trend through data analysis and have published their findings1. This pattern is further investigated by a separate Q and A article2 published by Yasuhiro Ito, Yuri E. Nikiforov, Martin Schlumberger, and Riccardo Vigneri. Both works do not completely rule out the idea that incidence of thyroid cancer is increasing, however they both support the claim that the trend is most likely due to an increase in detection of the cancer through improved diagnostic procedures.

Saturday, May 10, 2014

Multitarget Stool DNA Testing for Colorectal-Cancer Screening

Earlier this year the FDA’s Molecular and Clinical Genetics Panel of the Medical Devices Advisory Committee determined that Exact Science Corp’s new stool based DNA test Cologaurd, a non-invasive colorectal cancer screening test, had demonstrated effectiveness, safety and low risk. Why is this important? Cologuard screens for colorectal cancer, a cancer that continues to be a major cause of death to men and women in the United States. It kills up to 600,000 people per year. As the current screening strategies for colorectal cancer have been found to be costly scientists working for Exact Science Corp. have been researching cost-effective tests with greater sensitivity.  This research led to a simple, non-invasive test with high sensitivity for both colorectal cancer and advanced precancerous lesions. The clinical trial for Cologuard was quite successful compared to the standard fecal immunochemical test (FIT), which is the current standard colorectal screening test.

Thursday, May 8, 2014

Examination of Paralogue Genes

    In preparation for my project with Sonya, I discovered a study on a paralogue to the L3MBTL1 gene.  This gene is critical to the randomized clinical trial entitled, "Physical Activity and
Breast Cancer Survival: an epigenetic link through reduced methylation of a tumor suppressor gene L3MBTL1".  If this study we are evaluating has significance, then it requires this gene encode a tumor suppressor.  A study of a paralogue gene entitled, "Loss, mutation, and deregulation of L3MBTL4 in breast cancer" provides evidence that L3MBTL4 is a tumor suppressor gene and implies our gene of interest the L3MBT1 is one as well.

Sunscreen and Skin Cancer: Analysis of Single Ingredients

As discussed in my previous blog post, sunscreen is made up of chemicals that many of us do not pay attention to. While some believe ignorance is bliss, Donathan G. Beasley and Thomas A. Meyer think otherwise. This mindset is exemplified in their analysis of the attenuation profiles of individual sunscreen ingredients. (For those who are confused by the word “attenuation”, here is the Merriam Webster definition of “attenuate”: To make something weaker or less in amount, effect, or force)

Imatinib Resistance and GIST

     For our cancer project Braelyn and I will be studying Gastrointestinal Stromal Cancer. James Bradner, the DeNardo lecturer that came to speak to us mentioned this type of cancer and one of its treatments: Gleevac otherwise known as imatinib. One of the most interesting parts of this type of cancer is its high response rate to treatment by the imatinib kinase inhibitor but, this treatment doesn't always work.

Tuesday, May 6, 2014

Malignant Melanoma Staging and Advances in Chemical Agents.

This is my first blog post regarding my cancer project with Ellie Pringle.  First things first….I wanted to learn the stages and classifications of developing malignant melanoma.  An article from the National Cancer Institute gave an overview of the stages of skin cancer and the symptoms associated with each.  A melanocyte is a melanin-producing cell that is located in the bottom layer of our skin’s epidermis.  Melanin is the primary determinant of skin color in humans and is a derivative of the amino acid tyrosine. 

The Role of RbAp46 in Preventing Breast Cancer


In my last post, I discussed the morphology of the breast tissue and how it further differentiates into more advanced lobule types when when become pregnant. The article that discussed this postulated that this differentiation confers resistance to breast cancer mutations because there are less basic epithelial cells in the more complex breast tissue, which means they are less likely to be taken over and grow out of control when faced with mutagens (Russo, 2001). This is one hypothesis for why parous woman, women who have carried out a full pregnancy, have decreased rates of breast cancer. However, this article never gave any proof for what changes occur in the more complex lob 2-4 tissue, which makes it hard to fully accept this theory.

Monday, May 5, 2014

The Cure for One Cancer is the Cause of Another: Part 2

This blog post is a continuation of my last post so I will first review what was found in the first post. A 76-year-old man was diagnosed with stage IV BRAF V600K mutant melanoma. He was put on a BRAF mutant inhibitor (vemurafenib or PLX4032) and responded well to the chemotherapy until it was discovered that the drug was causing the patient to develop chronic melomoncytic leukemia. Analysis of the patient’s leukemia cells showed an upstream mutation in the NRAS oncoprotein. The doctors then hypothesized that vemurafenib was causing the hyper activation of ERK (Map Kinase) and stimulating the growth of preexisting NRAS-mutated chronic myelomonocytic leukemia cells. This is now widely known as the paradoxical activation of ERK.

iCancer — Are cell phones increasing our risk?

Nobody Likes Cancer . . . But Everybody Likes Cell Phones!

We hear about it everyday. New foods or products are constantly putting us at risk of developing cancer, and what is worse is that many of these claims have very little support behind them. One of the most common theories that preferentially puts our generation at risk is the idea that the cell phones put us at a greater risk of developing cancer. But is this true? One of the biggest problems surrounding this topic is the vide variety of tests and results available within the scientific community. From this most big-name institutions such as the American Cancer Society(ACS) and National Cancer Institute have chosen to say that there is little scientific evidence supporting the claims, whereas others like the World Health Organization choose to list cellular devices as a potential carcinogen on the IARC's 2B list (which is essentially a watch list). Rather than generating more data that is likely to be inconclusive, I have decided to break the argument down on a few different levels in order to reach my own conclusion.
Figure 1: Source, Marion Institute

Sunday, May 4, 2014

Heterogeneity of the Circulating Tumor Cell

            Carlos Rivera and I are researching the correlation between circulating tumor cell (CTC) counts and the progression of the cancer. These CTCs are seed cells that have shed from the primary tumor and circulate through the bloodstream and are the primary means through which metastases spread. Furthermore, they are also fairly easy to collect as they only require a blood draw. Due to their utility, there has recently been a great deal of development in the study of CTCs as well as their application in treatment. However, one particular aspect that caught my attention in my research was their heterogeneity. One article that I found was helpful on the subject explained how a degree of heterogeneity was achieved through cytomorphological similarities between the CTCs and the primary tumor cell.

Hints for Screening Tests in Familial Thyroid Cancer

There is a rare form of thyroid cancer known as medullary thyroid carcinoma (MTC), which can be familial; meaning that it is a germ line cancer.  MTC only accounts to about 3-10% of all thyroid cancers but is responsible for about 13% of all deaths from a thyroid cancer. This study looked at hereditary MTC as well as multiple endocrine neoplasia 2 MEN 2 (A and B), sub-classifications of MTC.  MEN is a medical disorder where tumors grow in endocrine organs and cause problems originating in the thyroid.  Type 2A is a condition in which excess parathyroid hormone is secreted and type 2B can cause neurofibromatosis.  The findings from this paper suggest that inherited MTC is detected earlier in life and treated, where as sporadic MTC is not detectable and results in more deaths..

Pre-leukemic HSCs bearing mutated DNMT3A undergo multilineage differentiation and evade chemotherapy

In my previous post, I introduced Hematopoietic Stem Cells (HSCs) and their involvement in acute myeloid leukemia (AML). I mentioned a very important finding from Shlush’s paper in Nature that mutated DNMT3A is present in the pre-leukemic ancestral cells which give rise to the T cells and AML cells found at the time of diagnosis of the disease.

I now go further to discuss the types of non-leukemic HSC populations in which the mutated DNMT3A first arises. Researchers isolated non-leukemic hematopoietic stem and progenitor cell populations from 11 mutated DNMT3A/NPM1c AML patients. Note that progenitor cells are relatively immature cells that are precursors to a fully differentiated cell of the same tissue type. The cells isolated from these patients were the hemotopoietic stem cells/multipotent progenitors (HSCs/MPPs), multilymphoid progenitors (MLPs), common myeloid progenitors (CMPs), granulocyte monocyte progenitors (GMPs), megakaryocyte erythroid progenitors (MEPs), as well as mature B, T and natural killer (NK) cells within a CD33cell fraction and CD33+ AML blasts. These were highly purified, phenotypically normal cell populations that were assessed by ddPCR for allele frequencies of DNMT3A and NPM1c, both of which were found together in CD33+ AML blasts but DNMT3A was also found alone at variable allele frequency (mean is 24.6%) across the spectrum of mature and progenitor cells.

The Role of Mc1r in UV-induced tanning


            Michelle Fat and I are doing our project on a topic regarding skin cancer, and so this blog post will focus on the role of melanin, and more specifically, the pathway for producing melanin involving the melanocortin 1 receptor (MC1R) and melanocyte stimulating hormone (MSH). The article, “Topical drug rescue strategy and skin protection based on the role of MC1R in UV-induced tanning,” discusses an experiment done on mice to examine the role of MSH-MC1R in producing melanin in response to UV exposure, as well as the effect of forskolin as a drug to protect skin.  
            Ultraviolet radiation from sun exposure is mostly Ultraviolet A, which can penetrate into the skin and cause indirect DNA damage through single-strand breaks and DNA-protein crosslinks. 5% of DNA photodamage is due to UVB, which is directly absorbed by the DNA and can cause structural damage. In response to UV exposure, melanin is produced in melanosomes (of melanocytes) and is transported to keratinocytes to be stored in the perinuclear area and act as a shield for DNA from UV rays. Melanin is made of lighter red/yellow pheomelanin and darker brown/black eumelanin. The difference in the color of people’s skin is based on how much melanin is produced, what type is produced, and the size and structure of it.