Monday, January 29, 2024

Week 3 - Physiology of Cancer: Elaborate 2

 

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DNA Discussion Prompt:

We are going to refer back once again to our central prompt about cancer and genetic testing:

Your friend tells you she recently had genetic testing done, and her doctor said she /

Your friend is unsure what this means and is worried she will definitely get breast cancer later in life.

We've now discussed many reasons why your friend would not be 100% guaranteed to get cancer - particularly not aggressive cancer - based on just one mutation.  How would you explain at least a few of those reasons to your friend?  You might consider how her risk of cancer relates to topics like:

  • Cyclins
  • Tumor Suppressors
  • Oncogenes
  • Cell Specialization
  • Angiogenesis
  • Metastasis
  • Adherens Junctions and Desmosomes

In a moment, I'm going to ask you to share your individual thoughts in an application question.  This discussion is an opportunity to share ideas with some colleagues and get clarifications before responding individually!

 

             Based on just one genetic mutation my friend may not get cancer.Oncogene is a mutated gene that has the potential to cause cancer. The normal healthy adult their genetic and cellular mechanisms can prevent the growth and spread of the cancer mutation. Cyclins control the progression of the cell cycle by activating particular enzymes one kinase in humans activates the proteins that carry out DNA replication.In healthy adult the DNA damage everyday which called mismatch ,but  DNA fixed by itself.The error form different form sometime nucleotide match the correct way. Each nucleotide contain base each DNA during replication the enzyme DNA polymerase help to bring the right partner pair with every base. The enzyme catches the mismatch and repair it right away which called mismatch repair.  The healthy adult body the DNA mismatch repair by it self. Sometime lots of different molecules could cause chemical changes to nucleotide which was the trigger such as exposure from our environment chemicals , substances , UV light, contain chemical compound in smokes that caused DNA damage.  But our body have specific enzyme to reverse or correct the damage. Our body cell also has more general repair pathways . Just one base is damaged it can usually fixed by a process called base excision repair.  

If  double strand DNA is not damage she may not get cancer.   Cancer needs a blood supply to grow or spread  is called angiogenesis. Metastasis is spreading the cancer other part of the body.



  Cyclins control the progression of the cell cycle by activating particular enzymes—cyclin dependent kinases. Those kinases act on different protein structures that play large roles in the cell cycle. For example,

Scientist Spotlight #3

 

Scientist Spotlight #3

            After listening Brion Randolph's podcast about save the cats  and the article "Doctors study tumors’ genetic makeup to guide cancer treatment " I felt more curious about cell and how the abnormal destroy the DNA in the body. Because of little six kitten Brion Randolph's life had changed which put him get into career of science. Grade 9 student come up with great idea working on science project I am really impressed about him. Listening about his story I gain more courage in study about science.

           When reading about  genetic makeup to guide cancer treatment article I found out the complexity of the cancer. In the past I don't fully understand how and why patient get cancer. After watching the video of how DNA  damage ,how the DNA fixed by itself. I have learned that normal healthy adult  body cells can able to fix most of DNA damage problems, most of the time.  

               Surprisingly, the technology play important role in diagnostic and giving treatment for cancer patient, With the help of the technology the tumor able to detect more than 300 genetic mutation DNA.  The nuclear medicine  and nuclear diagnostic technology is not only useful in scientific learning in cancer cell but also effective in providing treatment.

           Sadly, the charges of vitro chemo sensitivity and tumor profiling tests for cancer is not covered by insurance. Although the diagnostic technology of cancer is advance the outcome of cancer five years survival rate are still low.  However, I have learned about the advance genetic mutation therapy is the biggest breakthrough in lung-cancer treatments.

 

Brion Randolph: Curiosity Saves The Cats ( podcast script)

 
Brion Randolph: Curiosity Saves The Cats

Hi everyone, I'm Ben Lillie and welcome to the Story Collider where we bring you true personal stories about science. This week’s story is from Brion Randolph. It was recorded in March 2016 at the Atlanta Shakespeare Tavern in Atlanta, Georgia as the part of the Atlanta Science Festival.

So, it all started with the cat's meow, and who would have ever thought that 6 little kittens in the box would have change my life and put me into a career of science. 

So, when I was in 9th grade, I was surrounded by science -- my mother was a science teacher, and all of her friends were science teachers. So, I kind of had cool science projects going through school. And, I worked at the local veterinarian office. And working at that office, I would come in on the weekends, and I was the one that, you
know, would have to, basically, clean the stalls, you know, scoop the poop and all that good stuff, you know. Really exciting job. And I walk in, one day, and on the stoop, there is this box, and inside of that box were 6 little kittens. So I took them inside with me, and I put them in one of the kennels, and then the next day when the veterinarian came in, I shared with him that I found these kittens and what do we do with them? He said, "You know, normally, what we'll do is
we'll send them over to the pound, and they either get adopted or get euthanized at some point." And I said, "I don't like that idea," I said, "what else can we do?" So, we came up with an idea, you know, me in this whole science project stuff, you know. I wanted to have another cool science project, and so we came up with this idea that we would take those kittens, we would put each one in a different kennel, and we would feed them different types of food. So, we had like Wal-Mart brand and Purina and science diet that he sold at his office, you know, that was the superior food. So, we did that, and he taught me things like how you determine a healthy kitten that growing like it should. So, we weight the cats, we looked at their coat quality, we looked at blood work, and long story short I ended up as a 9th grader putting together a book that big where I wrote up this
project, and did a science project that took me all the way to the state finals, and to the South Carolina Junior Academy of Science where I got to do my first oral presentation. And of course, I was nervous about all of that, but man what an experience! Because who knew that that then would lead to later in life all the things that I do, all the presentations, and so for all that I get to do. So I knew at that point, something in science would be good, and than I ran into this
excellent math teacher, who really just got me excited about math and started to participating in some of the clubs in the school – one of the engineering clubs in particular. We got to go on field trips, and we went to VC summer power plant, and we went to savanna river plant. And I thought it was kind of cool, we were going to all these
nuclear plants, but they can't tell you anything about it. Because it is a secret. So, I decided to go in a nuclear engineering. So, I went University of Tennessee and majored in nuclear engineering, and I'm going through this curriculum which is really focused on,
you know, how do you make nuclear power, also about waste management, and things like that. And this physician comes over to us one day and gives us a lecture about physics behind medical imaging. And a lot of that had to do with like PET scans and CT scans and all of the different imaging that they do in people who has cancer, for example. And so, the interesting thing about that is that approached him and he said, "why don't you come over here and just volunteer?" What I did not know is there was an ulterio motive here. But I went over, and I volunteered with him, and in the department he
started putting me with -- he did 2 things he put me with one of PhD scientist -- and then
he also -- who was doing a lot of algorithms and calculations and things which would just write up my ally. But he also put me with the technicians who were doing the scans. And so one of the things that I noticed is that they have a lot of papers they filed out. You know. They calculate all of these things, and they fill out these forms, and than they give to the doctor, and then the doctor would somehow make a decision on what to do with a patient based on all these calculations they did. And I said their kind of engineering going "Really? Hand calculations? I mean you know there are excel spread sheets, there is macros you can do." So, you know I took all of that, and made these spread sheets and macros, so that the text would plug in the values, and it would speed out this report for them that they can just give it to the doctor. And they just thought that that was amazing. So, the trade off was they let me seeing patients with them. And so I started learning how to do bone scans and how to do PET scans from a technician perspective. And one day I remember that I was doing a bone scan with the tech, the tech stepped out the room, and the guy on the table goes, "hey, hey kid, hey, want to try some shine" And so you know I kind of looked at him "Excuse me? Excuse me. I was in Tennessee." So, he goes, "Moon shine, you know moon shine, my body is
make it up in the hills, but shhh.. You can't tell anyone about that". He was like, "I got some out in the truck if you want to try it." So, I didn’t try it, but long story short is later that day I started going to the tumor boards and things at the hospital, and this man's case came up, it turn out he had metastatic prostate cancer. And that's why he was getting a
bone scan, and it was kind of cool for me because you know they are talking all of the doctor talk about this patient, and what they are going to do. And I'm thinking, "I bet they don't know, he makes a moon shine." So, that kind of hit home with me because I started
thinking, "man, really it's kind of cool to understand how that machine works, but it would be even cooler to be able to put that man story together with the machine." And so I sat down one day with Dr. Smith and I told him that -- you know -- my experience and how I enjoyed all of these things. And he kind of looked at me and said,"You know, you are turning to the dark side, right?" And I didn't quite understand it, but
what he was telling me was that I really wanted to do medicine, and be able to put it all that together. And so, I took that from him and stayed, and did my masters degree, he set on my thesis committee with me, and eventually, then ended up applying and going to a medical school. So, then I get into medical school, and I'm going through these rotations, and I think, well naturally nuclear engineering than I should probably be radiation oncologist, right? So, I do bunch of rotation in radiation oncologist, and it was okay, I mean, I enjoyed it. But then I got in my medicine rotation, and I had this resident that was
absolutely amazing, I mean he just taught you everything, and he seemed like he knew everything. And in medicine the cool things don’t really happen in the day, it's at night. So, as a medical student you didn’t have to take call at that time, but I decided I would
because I would learn more. And so I stayed the night, and they didn't even have call room for me to really stay in, so I had to makeshift little cot that I made. And then every time he got called out for something in ER or whatever I went with him. Well, one night while I was with him on call, he asked me to go in and check on a certain patient; and this
was a guy who had been in a hospital for about a week or so, and we are at the VA hospital, and he had lungs cancer, and he was pretty sick. And so, I just sat there when I went to check on him, he asked me to sit down for a minute, and I sat down, and I kind of talk to him for a while, and I don’t remember his whole story, but what I do remember is that he told me you know that "I would really like to just go outside. I haven't left this room in like over a week." And I said "okay" you know I'm naive, I'm medical student "yeah, we 'll do that." So I go out and tell the nurses there, and they like "" no, you won’t do that. This man has IV and antibiotics, he needs oxygen, we can't do that." So, I was persistent though. Over the next few days I kept approaching different nurses and asking them if they would help me out and take this man outside. And so finally, I found one nurse who agreed, and so we got him on a wheelchair, and we rolled him outside to the
front of the VA hospital. And much to our surprise, he stands up on his own, turns and looks at the American flag, gives it a salute and sits back down in a chair and says, "That's all I needed." So we took him back inside, and the next morning he dies. But that moment told me I needed to be an oncologist because what’ve I realized was that
I could help someone no matter what their situation was. And so today I get to give cures to cancer, I get to look at new drugs through research, and sometimes I just get to hold someone's hand. Sometimes I have to see them take that last breath, but I know their story, and I've been there with. So, science for me has brought hope, and the ability to deliver hope every day to people that I encounter. And whether it's rescuing 6 kittens or whether it's giving out a new cure or simply a salute. That's what science means to me.
Thank you.
Applause

That was Brion Randolph. Brion is currently the Chief of Medical Oncology at Cancer
Treatment Centers of America in Union, GA. He joins CTCA as a medical oncologist and
hematologist when hospital opened in August, 2012, and he is now a Chief of Medical
Oncology. He also serves as Medical Director of Hematological Oncology. Randolph
lives in Union with his wife and 2 children. He has passion for music and a performing
arts, and as a drum major he had the opportunity to lead the UT band in 1993 in inaugural
parade for Bill Clinton.
Annotations

M Phase of the Cell Cycle

Overview of Cell Structure

What happens when your DNA is damaged? - Monica Menesini

Doctors study tumors’ genetic makeup to guide cancer treatment

 copy from NewYork Time Articles ( for learning purpose )
Health & Science
Doctors study tumors’ genetic makeup to guide cancer treatment

By Arlene Karidis
March 9, 2015 at 1:41 p.m. EDT
March 9, 2015 at 1:41 p.m. EDT

cancer cell made in 3d software (iStock)

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When Jen Morey was diagnosed with colon cancer in June 2013, her oncologist began treating her with a chemotherapy usually prescribed for that type of cancer. But after a couple of months, the malignancy was still growing, and rapidly. The therapy was failing.

So her doctor ordered a test to identify aspects of the tumor’s genetic makeup that might be fueling its growth.

Morey’s oncologist was surprised when the tumor profile test, as the technology is called, showed that the cancerous cells in her colon had a genetic mutation found almost exclusively in breast cancer. So he started her on a drug used mostly for fighting breast cancer.

Tumor profile tests are considered experimental, so they are typically reserved for patients, such as Morey, who have advanced cancer and no treatment options that seem likely to be effective.

Although some studies have found the tests promising, researchers and organizations including the American Society of Clinical Oncology believe further investigation is needed to determine their effectiveness.

In one clinical trial, tumor profiling identified a variety of abnormal genes in 31 lung cancer patients who had no evidence of genetic alterations based on standard tests. 

A drug to target the abnormality was available for eight of these patients; six received the therapy, and all six improved. Improvements ranged from stabilization (the cancer stopped growing) to tumor shrinkage.

In another trial, treatments prompted by tumor profiling benefited 10 of 25 metastatic cancer patients who had run out of other options.
How malignancies grow

Figuring out why and how malignancies grow is complicated, because there may be hundreds of abnormally behaving genes within a single cancer cell though only a few of them may be fueling the cancer. Furthermore, a patient’s abnormal cells are unique to that person, explained Michael Pishvaian, Morey’s oncologist at Georgetown Lombardi Comprehensive Cancer Center.

“Determining what is driving a person’s cancer can be like looking for a needle in a haystack,” he said.

Morey’s lab work found that needle.

She stabilized quickly on the drug that targeted the “breast-cancer” gene mutation. The drug was easier to tolerate than many chemotherapies because it attacks only cancer cells, sparing healthy ones. And because it might boost the effectiveness of the colon-cancer drug she was already receiving, she remained on the original treatment along with the new drug.

“I was hopeful for the first time in a long time,” said Morey, 38, a critical-care nurse who lives in the Friendship section of Anne Arundel County.

A CT scan in December showed that the new effort to fight the aggressive HER2 gene seemed to be working. Morey remains stable, meaning the cancer is no longer growing. She returned to work in late January after having gone on leave earlier in her treatment regimen.

“I am in this very small percentage, so everything we do is out of the box. But I am hopeful that this combination will continue to work,” she said. “And if not, there are still other drugs to try.”
Another approach

"Individualized medicine" has been a buzzword in the world of cancer care for years, but the concept has been gaining increased currency. President Obama endorsed it in his State of the Union address in January, referring to it as "precision medicine." In February, Inova said it planned to build a major complex in Northern Virginia devoted to genomics and personalized medicine.

With the continued push to find the right drug for the right person, increasingly sophisticated diagnostics are evolving, such as the tumor profiling tests. Tumor profiling is done by photographing DNA that has been extracted from a piece of a biopsy. The data captured in the photos is used to detect abnormalities. The technology has sometimes detected more than 300 genetic mutations in a single tumor.

 

Another approach is chemo sensitivity testing, in which part of a tumor is placed in a petri dish or test tubes with different drugs or drug combinations. The goal is to see what might kill every malignant cell. Like tumor profiling, this approach is ordered for advanced-cancer patients after all treatment options have failed. Both test types are used in most solid-tumor cancers, including disease of the breast, ovaries, prostate and colon. And there are versions for blood cancers such as leukemia and lymphoma.

In one trial where drugs were selected through chemo sensitivity testing, the tumors of 20 of 31 people with lung cancer stopped growing, shrank or disappeared. This was slightly more than double the response that standard drugs would be expected to produce in similar patients.

In a study involving 30 women with metastatic breast cancer, chemo sensitivity testing identified a combination of drugs that shrank tumors by at least 30 percent in half of the patients. The length of time until the disease progressed more than doubled.

Victor Priego, a Bethesda oncologist, orders tumor profiling or chemo sensitivity testing for almost 20 percent of his hardest-to-treat patients.

“Chemo sensitivity tests have not hit mainstream oncology because they have not been validated through many rigorous clinical trials. But I use a lab in California that has been rather consistently on the mark when you would not expect the suggested drugs to work. And this is with most cancer types,” he said.
A test-tube alternative

Alex Spira, a Fairfax oncologist and researcher, believes there is merit to tumor profiling, but he doubts the reliability of chemo sensitivity tests. “What happens to a tumor when it’s treated in a test tube doesn’t directly correlate with what happens in patients,” he said.

He is less skeptical about the reliability of a similar tool where biopsied portions of a tumor are implanted in mice, as research shows that a human malignancy appears to grow almost identically in a mouse as in a person.

“We can put a small amount of one tumor into 100 mice, to test many drugs and drug combinations,” said Ronnie Morris, founder of Champions, the Baltimore-based lab that developed the mouse avatar test. He believes the technology will accelerate scientific learning.

“Clinical trials are expensive and take years, and the tested drugs do not make it to market 92 percent of the time because they were not proven effective,” he said. “Meanwhile, a drug may be a good one, but in other populations or other combinations.”

In one small trial using the mouse avatar, treatments were identified for 22 of 29 patients. Six of the 22 died before the testing was completed, but of the remaining 16 people, 13 responded to the identified drugs.

There are drawbacks to the mouse avatar; it costs $10,000 to $12,000 and is not covered by insurance. Also, a tissue sample is not always obtainable because it is in an inaccessible location, which is also the case with in vitro chemo sensitivity tests. And while results of in vitro chemo sensitivity and tumor profiling tests are back in one to two weeks, results using mice take four months.

 

“This diagnostic would be for advanced cancer patients,” Spira said. “But they don’t have time to wait.”

Charges for in vitro chemo sensitivity and tumor profiling tests range from $4,000 to $7,000.They are often not covered by insurance.
Do they work?

And then there is the question of whether they really work.

The American Society of Clinical Oncology believes there is insufficient evidence to support use of chemo sensitivity tests in general oncology practice — i.e., they should be restricted to clinical trials. But the organization states, "Because the . . . strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority." ASCO is working on a position on tumor profiling.

Tumor profiling and chemo sensitivity tests do not require Food and Drug Administration approval.

“So we can’t say, based on our experience, whether [these particular diagnostics] can predict treatment well,” said Elizabeth Mansfield, deputy office director for personalized medicine in the Office of In Vitro Diagnostics and Radiological Health at the FDA.

Concerned about a growing number of products that have not received rigorous scrutiny, the FDA is working to take on review and approval oversight.

Five percent of Spira’s patients who underwent testing have benefited from treatments guided by tumor profiling findings, though he said outcomes were dramatic. He cited one lung cancer patient whose tumor disappeared five days after beginning a new treatment.

Pishvaian, Morey’s oncologist, and Priego, the oncologist in Bethesda, say a small number of their patients have responded well to drugs selected using tumor profiling.
Cancer death rates

Cancer death rates in the United States have slowly dropped. In 1950, the age-adjusted death rate for all cancers was 193.9 per 100,000 people, according to the National Center for Health Statistics. In 2013, the rate was 163.2, a decline of 16 percent in 63 years.

Five-year survival rates are low, however, for metastatic cancers. Five-year survival for Stage 4 lung cancer is 1 percent, according to the American Cancer Society. Stage 4 colorectal cancer has an 11 percent survival rate, and Stage 4 breast cancer a 22 percent five-year survival rate.

Cancer researchers and oncologists such as Spira believe that one focus of the past 20 years — to study the genetic makeup and behavior of tumors — will lead to better outcomes.

Spira cites gefitinib, discovered through tumor profiling to target a mutation in lung cancer. (A similar drug, Tarceva, is now used by many people with advanced lung cancer.)

“For patients with this particular lung-cancer mutation, this discovery is profound. It is, to date, the biggest breakthrough in lung-cancer treatments,” he said. “It is a constant battle to find and target genes that are causing the problem. But the way to get closer to better outcomes is to concentrate on genetics.”

“For now, with what we are learning, at least we have options to try when there were no others,” he said. “In time, we will find more Tarceva-like drugs, and for cancers beyond lung cancer.”

Karidis is a freelance writer.

 
 


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