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Can Elephants Help Fight Cancer?

Reporter: Gail S. Thornton, M.A.

 

 

This paragraph is excerpted from the American Technion Society Facebook page.

Professor Avi Schroeder and Dr. Josh Schiffman of the The University of Utah are working with elephants at Utah’s Hogle Zoo on a possible new tool to fight against lung, bone, breast, and other cancers. Dr. Schiffman found that p53, a cancer-suppressing protein, is far more prevalent in elephants, which rarely develop cancer. Prof. Schroeder is now working to manufacture the protein in nanoparticles to begin preclinical testing.


This article is excerpted from The Salt Lake Tribune, May 2, 2019.

Earth’s biggest, smallest, oddest life forms are getting new attention from scientists. A Utah author explores what they’re learning.

Published: May 2, 2019

Researchers have long ignored superlative life forms — the biggest, the tiniest, ones that can survive extremes — as outliers, Utah author Matthew D. LaPlante says.

But they’re now realizing the value of studying nature’s “oddballs,” he adds, which are helping scientists discover how to better fight disease and aging, understand the history of life on this planet and how we might reach others.

LaPlante’s new book, “Superlative: The Biology of Extremes” was released this week. On Friday at 7 p.m., the associate professor of journalistic writing at Utah State University will read from “Superlative” and talk about his work at The King’s English Bookshop, 1511 S. 1500 East, Salt Lake City. The event is free and open to the public.

The co-writer of several books on the intersection of scientific discovery and society, LaPlante now is working with Harvard geneticist David Sinclair on a book about human longevity. “Superlative” from BenBella Books is the first solo book by LaPlante, a former reporter for The Salt Lake Tribune.

As he surveys unusual life around the earth, there are stops in Utah — from Pando, the aspen clone in Sevier County believed to be the single most massive living organism known on Earth, to pop-up appearances by researchers at the University of Utah and elephants at Hogle Zoo in Salt Lake City.

Vast sequences of the genetic coding that humans share with elephants still perform similar functions in each species, LaPlante explains. And long after the two diverged, both developed the same genetic solution for the oxygen needs of a larger brain.

So there’s reason to believe that responses elephants have evolved — such as rarely developing cancer — might be spurred in humans.

The potential within a genome for such new traits to develop is at the heart of comparative genomics — and at the work of Utah pediatric oncologist Josh Schiffman.

This excerpt from “Superlative” explains how Schiffman began working with Hogle Zoo’s African elephants — the largest living land mammals — to fight cancer.

It all started in the summer of 2012, when [pediatric oncologist Josh] Schiffman’s beloved dog, Rhody, passed away [due] to histiocytosis, a condition that attacks the cells of skin and connective tissue. “It was the only time my wife has ever seen me cry,” he told me. “Rhody was like our first child.”

Schiffman had heard dogs like his had an elevated risk of cancer, but it wasn’t until after Rhody’s death that he learned just how elevated it was. Bernese mountain dogs who live to the age of ten have a 50 percent risk of dying from cancer.

“Suddenly it dawned on me there was this whole other world, this young field of comparative oncology,” he said, “and I was pulled into the idea of being a pioneer and maybe a leader to help move things along.”

Schiffman had long been intrigued by the fact that size doesn’t appear to correlate to cancer rates — a phenomenon known as “Peto’s Paradox,” named for Oxford University epidemiologist Richard Peto. But when Schiffman took his children on an outing to Utah’s Hogle Zoo — the same place I sometimes go to have lunch with my elephant friend, Zuri — everything came together.

A keeper named Eric Peterson had just finished giving a talk to a crowd of visitors, mentioning in passing that the zoo’s elephants have been trained to allow the veterinary staff to take small samples of blood from a vein behind their ears. As the crowd dispersed, an angular, excited man approached him.

“I’ve got a strange question,” Schiffman said.

“We’ve heard them all,” Peterson replied.

“OK then — how do I get me some of that elephant blood?” Schiffman asked.

Peterson contemplated calling security. Instead, after a bit of explanation from Schiffman, the zookeeper told the inquisitive doctor he’d look into it. Two and a half months later, the zoo’s institutional review board gave its blessing to Schiffman’s request.

Things moved fast after that.

(Steve Griffin | Tribune file photo) Lab specialists Lauren Donovan Cristhian Toruno, Lisa Abegglen and researcher Joshua Schiffman, from left, are testing the effects of elephant gene p53 (EP53) in human cancer cells at the Huntsman Cancer Institute.
(Steve Griffin | Tribune file photo) Lab specialists Lauren Donovan Cristhian Toruno, Lisa Abegglen and researcher Joshua Schiffman, from left, are testing the effects of elephant gene p53 (EP53) in human cancer cells at the Huntsman Cancer Institute.

Cancer develops in part because cells divide. During each division the cells must make a copy of their DNA, and once in a while, for various reasons, those copies include a mistake. The more cells divide, the greater the odds of an error, and the more prone an error is to be duplicated again and again.

And elephant cells? Those things are dividing like crazy. Based on the number of cell divisions elephants need to get from Zuri’s size when we met to the size she is now, in just a few short years, it stands to reason they should get lots of cancer. Yet they almost never do.

“Going from 300 pounds as a calf to more than 10,000 pounds, gaining three-plus pounds a day, they’re growing so quickly, so big and so fast — baby elephants really shouldn’t make it to adulthood,” Schiffman said. “They should have 100 times the cancer. Just by chance alone, elephants should be dropping dead all over the place.” Indeed, he said, they should probably die of cancer before they’re even old enough to reproduce. “They should be extinct!”

Already, comparative oncologists suspected the exceptionally low rate of cancer in elephants had something to do with p53, a gene whose human analog is a known cancer suppressor. Most humans have one copy — two alleles — of the gene. Those with an inherited condition known as Li–Fraumeni syndrome, however, have just one allele — and a nearly 100 percent chance of getting cancer. The logical conclusion is more p53 alleles mean a better chance of staving off cancer. And elephants, it turns out, have twenty of them.

The big find that came from Schiffman’s exploration of the elephant blood he got at the zoo, though, was not just that there were more of these genes in elephants, but that the genes behaved a little bit differently, too.

In humans, the gene’s first approach for suppressing tumor growth is to try to repair faulty cells — the sort that cause cancer. So, at first, Schiffman’s team assumed having more p53 genes meant elephants had bigger repair crews. With the goal of watching those crews in action, the researchers exposed the elephant cells to radiation, causing DNA damage. But they noticed that, instead of trying to fix what was broken, the elephant cells seemed to grow something of a conscience.

To understand this, it’s helpful to think about how you’d respond in a zombie apocalypse. Of course you’d fight long and hard to keep from being infected, right? But if a zombie was about to chomp down on your arm, and there was nothing you could do to stop it, and if you had but one bullet remaining in your gun —and a few moments to consider what you might do to your fellow humans as a part of the legion of the undead — what would you do?

That’s what elephant cells do, too. Under the directive of p53, mutated cells don’t put up a fight. Upon recognizing the inevitability of malignant mutation, they take their own lives in a process known as apoptosis.

And they don’t just do this for one kind of cancer. The p53 gene apparently programs cells to do this in response to all kinds of malignantly mutated cells in elephants—a finding that flies in the face of the conventional assumption that there is no one singular cure for the complex group of disorders we call cancer.

When I first met Schiffman in 2016, he was brimming with excitement about the potential elephants have to help us understand cancer. He was also very cautious not to suggest he was anywhere near a cure, nor that he ever would be.

Just a few years later, though, Schiffman was speaking openly about his intention to rid the world of cancer. And, to that end, what’s happening in his lab is encouraging, to say the least.

He and his team have been injecting cancer cells with a synthetic version of a p53 protein modeled on the DNA he’s drawn from Zuri and other elephants from around the world. Viewed on time-lapse video, the results are unmistakable and amazing.

Breast cancer. Gone.

bone cancer. Gone.

Lung cancer. Gone.

One by one, each type of cancer cell falls victim to zombie-cell hara-kiri, shriveling and then exploding, and leaving nothing behind to mutate. Schiffman is now working with Avi Schroeder, an expert in nanomedical delivery systems at Technion-Israel Institute of Technology, to create tiny delivery vehicles to take the synthetic elephant protein into mammalian tumors.

If this was all the benefit we ever derived from studying elephants, it would be plenty.

But it’s not. Not at all.

Source:

https://www.sltrib.com/artsliving/2019/05/02/earths-biggest-smallest/?fbclid=IwAR09iwADrhUKkuoXDRMBHFIMstUESU3OBXxKeN0dTKwxapTUASWsv1T_kZI

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Elephants and cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

In 1992, I moved to the Washington DC area and attended a conference on new and projected trends in cancer care at the National Institutes of Health.

Researchers in Texas are now reporting that there may be a smarter way to combat cancer-associated KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations and possibly attack specific tumor types in a new targeted manner.

A new study at a single center in Japan found no significant differences in the rate of BRCA mutations between ovarian cancer patients with or without family histories of the mutations and recommends that BRCA1/2 testing be required for all ovarian cancer patients

 

Why Elephants Don’t Get Cancer

Blog | October 30, 2015 | Cancer and Genetics
By Deborah A. Boyle, RN, MSN, AOCNS, FAAN

Image © Marchenko Yevhen/ Shutterstock.com
In 1992, I moved to the Washington DC area and attended a conference on new and projected trends in cancer care at the National Institutes of Health. A pediatric immunologist who treated and studied rare genetically-based childhood illnesses told the audience of oncology nurses that in the future there will be no need for surgery, radiation, or systemic antineoplastic therapies to treat cancer. Rather, genetic molecular engineering will be used to stop and reverse early signs of cancer and counter carcinogenesis even at later stages. I sat in the audience and was awestruck by this forecast. I found it unfathomable that this could ever become a reality.
Fast forward to 2015, over 20 years later, and I read in the science column of the Los Angeles Times the story entitled, “Elephants’ Anti-Cancer Secret” (October 10, 2015, p.B2). Reporting on a study published in a recent issue of JAMA,1, 2 the columnist shares the finding that elephants (and other large mammals) rarely get cancer. Scientists recently revealed the potential reason for such.

African elephants have twenty copies of a gene called TP53, which produces a protein that suppresses tumor growth. Humans on the other hand, have only one copy of this gene. Collaborating with a zookeeper at Utah’s Hogle Zoo in Salt Lake City and the chief veterinarian for Ringling Bros. Barnum and Bailey Circus, the researchers also identified that elephants were able to make copies of TP53 such that they were incorporated into the genome over time. Additionally, when the elephants’ cells were exposed to radiation, cell death occurred at twice the rate of human cells.

In recent years, the advent of targeted therapies and the identification of genes associated with heightened cancer risk have put the spotlight on genetics in the management of cancer.

The implications of this research will undoubtedly help keep the focus on this critical area of cancer research. The scientists involved in this investigation posited that perhaps a drug could be created that mimics the actions of TP53 or that the insertion of TP53 genes into precancerous cells could reverse mutations. Since it took millions of years for the elephants of today to evolve, I guess waiting 20 years for this type of knowledge to come forth isn’t that long to wait.

I’ve become a believer in the profound possibility of genetics in cancer therapy. That physician I heard decades ago was “right on.”

REFERENCES

Abegglen LM, Caulin AF, Chan A, et al. (2015).
Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans.
JAMA, Oct 8:1-11. http://dx.doi.org:/10.1001/jama.2015.13134.
Greaves M, Ermini L. (2015).
Evolutionary Adaptation to Risk of Cancer: Evidence From Cancer Resistance in Elephants.
JAMA, Oct 8:1-3. http://dx.doi.org:/10.1001/jama.2015.13153.
– See more at: http://www.oncotherapynetwork.com/cancer-and-genetics/why-elephants-dont-get-cancer#sthash.5xGzcSFp.dpuf

 

Researchers Develop New Classification Model for Cancer-Associated KRAS Mutations

News | October 28, 2015 | Cancer and Genetics
By John Schieszer
Researchers in Texas are now reporting that there may be a smarter way to combat cancer-associated KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations and possibly attack specific tumor types in a new targeted manner. They are reporting that the use of biochemical profiling and sub classification of KRAS-driven cancers may lead to a more rational selection of therapies targeting specific KRAS isoforms or specific RAS effectors.
KRAS is one of the main members of the RAS family. About one-third of all human cancers, including a high percentage of pancreatic, lung, and colorectal cancers, are driven by mutations in RAS genes, which also make cells resistant to some available cancer therapies, according to the National Cancer Institute.

The UT Southwestern Medical Center researchers have developed a new classification for cancers caused by KRAS. They are investigating a new strategy based on models that the researchers developed to classify cancers caused by KRAS mutations, which cause cells to grow uncontrollably. Although KRAS-driven cancer mutations have long been a focus of cancer research, effective targeted therapies are not available.

“This work further supports the idea that not all oncogenic KRAS mutations function in the same way to cause cancer. The model we developed may help in sub classifying KRAS-mutant cancers so they can be treated more effectively, using therapies that are tailored to each mutation,” said Kenneth Westover, MD, who is an as Assistant Professor of Radiation Oncology and Biochemistry at the University of Texas Southwestern Medical Center, in a news release.1 “Furthermore, this study gives new fundamental understanding to why certain KRAS-mutant cancers, for example those containing the KRAS G13D mutation, behave as they do.”

The researchers, who have published their findings in Molecular Cancer Research, have characterized the most common KRAS mutants biochemically for substrate binding kinetics, intrinsic and GTPase-activating protein (GAP)–stimulated GTPase activities, and interactions with the RAS effector, RAF kinase. They report that KRAS G13D appears to show rapid nucleotide exchange kinetics compared with other mutants analyzed.2

In this study, the researchers evaluated eight of the most common KRAS mutants for key biochemical properties including nucleotide exchange rates, enzymatic activity, and binding activity related to a key signaling protein, RAF kinase. The researchers observed significant differences between the mutants, including about a tenfold increase in the rate of nucleotide exchange for the specific mutant KRAS G13D, highly variable KRAS enzymatic activities, and variability in affinity for RAF. They also determined high-resolution, three-dimensional X-ray crystal structures for several of the most common mutants, which led to a better understanding of some of the biochemical activities observed.

The researchers now plan to test their models in more complex experimental systems, such as genetically engineered cancer cell lines.

REFERENCES

UT Southwestern Medical Center. (2015).
Researchers develop classification model for cancers caused by most frequently mutated cancer gene.
Hunter JC, Manandhar A, Carrasco MA, et al. (2015).

Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations.
Molecular Cancer Research, Sep;13(9):1325-35.
– See more at: http://www.oncotherapynetwork.com/cancer-and-genetics/researchers-develop-new-classification-model-cancer-associated-kras-mutations#sthash.kkK8G0Mi.dpuf

 

 

 

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