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Efficiency of PARP inhibitors beyond BRCA mutations
Reporter
Irina Robu, PhD
PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase, which are developed for multiple indications but most visible is the treatment of cancer. Several forms of cancer are extra dependent on PARP than regular cells, making PARP an striking target for cancer therapy. PARP inhibitors seem to improve progression-free survival in women with recurrent platinum-sensitive cancer. In addition to their use in cancer therapy, PARP inhibitors can be a potential treatment for acute life-threatening diseases, such as stroke and myocardial infarction and neurodegenerative diseases.
With this knowledge in hand, Lee Kraus, director of the Green Center for Reproductive Biology Sciences at UT Southwestern his team identified a potential biomarker, DDX21 protein, which is required for the production of ribosomes in nucleoli. Nonetheless, DDX21 in the nucleolus requires PARP-1, which is targeted by existing PARP inhibitors. The use of these drugs, blocks DDX21, hence inhibiting ribosome production which as result means that enhanced DDX21 levels in the nucleolus could regulate cancers that might be the most responsive to PARP inhibitors.
Their data published in the journal Molecular Cell explains why breast cancer patients can be responsive to PARP inhibitors, even though they do not carry BRCA mutation. It is well known that the PARP inhibitors currently on the market such as AstraZeneca’s Lynparza, Clovis’ Rubraca and GSK’s Zejula work by disturbing PARP proteins that help repair damaged DNA in cell, hence steering cancer cells onto a path of annihilation. Since cancer cells are addicted to ribosomes to grow and make proteins to support cell division, inhibiting PARP proteins can slow down the growth of the cell.
Kraus’s group is currently working to design clinical trials with UT Southwestern oncologists to see if their hypothesis works. At the same time, they founded Ribon Therapeutics which is the first industrial biotech program going after PARP7, a protein also similarly activated by stress and cellular response mechanisms.
An Intelligent DNA Nanorobot to Fight Cancer by Targeting HER2 Expression
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
HER2 is an important prognostic biomarker for 20–30% of breast cancers, which is the most common cancer in women. Overexpression of the HER2 receptor stimulates breast cells to proliferate and differentiate uncontrollably, thereby enhancing the malignancy of breast cancer and resulting in a poor prognosis for affected individuals. Current therapies to suppress the overexpression of HER2 in breast cancer mainly involve treatment with HER2-specific monoclonal antibodies. However, these monoclonal anti-HER2 antibodies have severe side effects in clinical trials, such as diarrhea, abnormal liver function, and drug resistance. Removing HER2 from the plasma membrane or inhibiting the gene expression of HER2 is a promising alternative that could limit the malignancy of HER2-positive cancer cells.
DNA origami is an emerging field of DNA-based nanotechnology and intelligent DNA nanorobots show great promise in working as a drug delivery system in healthcare. Different DNA-based nanorobots have been developed as affordable and facile therapeutic drugs. In particular, many studies reported that a tetrahedral framework nucleic acid (tFNA) could serve as a promising DNA nanocarrier for many antitumor drugs, owing to its high biocompatibility and biosecurity. For example, tFNA was reported to effectively deliver paclitaxel or doxorubicin to cancer cells for reversing drug resistance, small interfering RNAs (siRNAs) have been modified into tFNA for targeted drug delivery. Moreover, the production and storage of tFNA are not complicated, and they can be quickly degraded in lysosomes by cells. Since both free HApt and tFNA can be diverted into lysosomes, so, combining the HApt and tFNA as a novel DNA nanorobot (namely, HApt-tFNA) can be an effective strategy to improve its delivery and therapeutic efficacy in treating HER2-positive breast cancer.
Researchers reported that a DNA framework-based intelligent DNA nanorobot for selective lysosomal degradation of tumor-specific proteins on cancer cells. An anti-HER2 aptamer (HApt) was site-specifically anchored on a tetrahedral framework nucleic acid (tFNA). This DNA nanorobot (HApt-tFNA) could target HER2-positive breast cancer cells and specifically induce the lysosomal degradation of the membrane protein HER2. An injection of the DNA nanorobot into a mouse model revealed that the presence of tFNA enhanced the stability and prolonged the blood circulation time of HApt, and HApt-tFNA could therefore drive HER2 into lysosomal degradation with a higher efficiency. The formation of the HER2-HApt-tFNA complexes resulted in the HER2-mediated endocytosis and digestion in lysosomes, which effectively reduced the amount of HER2 on the cell surfaces. An increased HER2 digestion through HApt-tFNA further induced cell apoptosis and arrested cell growth. Hence, this novel DNA nanorobot sheds new light on targeted protein degradation for precision breast cancer therapy.
It was previously reported that tFNA was degraded by lysosomes and could enhance cell autophagy. Results indicated that free Cy5-HApt and Cy5-HApt-tFNA could enter the lysosomes; thus, tFNA can be regarded as an efficient nanocarrier to transmit HApt into the target organelle. The DNA nanorobot composed of HApt and tFNA showed a higher stability and a more effective performance than free HApt against HER2-positive breast cancer cells. The PI3K/AKT pathway was inhibited when membrane-bound HER2 decreased in SK-BR-3 cells under the action of HApt-tFNA. The research findings suggest that tFNA can enhance the anticancer effects of HApt on SK-BR-3 cells; while HApt-tFNA can bind to HER2 specifically, the compounded HER2-HApt-tFNA complexes can then be transferred and degraded in lysosomes. After these processes, the accumulation of HER2 in the plasma membrane would decrease, which could also influence the downstream PI3K/AKT signaling pathway that is associated with cell growth and death.
However, some limitations need to be noted when interpreting the findings: (i) the cytotoxicity of the nanorobot on HER2-positive cancer cells was weak, and the anticancer effects between conventional monoclonal antibodies and HApt-tFNA was not compared; (ii) the differences in delivery efficiency between tFNA and other nanocarriers need to be confirmed; and (iii) the confirmation of anticancer effects of HApt-tFNA on tumors within animals remains challenging. Despite these limitations, the present study provided novel evidence of the biological effects of tFNA when combined with HApt. Although the stability and the anticancer effects of HApt-tFNA may require further improvement before clinical application, this study initiates a promising step toward the development of nanomedicines with novel and intelligent DNA nanorobots for tumor treatment.
Single-cell RNA-seq helps in finding intra-tumoral heterogeneity in pancreatic cancer
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Pancreatic cancer is a significant cause of cancer mortality; therefore, the development of early diagnostic strategies and effective treatment is essential. Improvements in imaging technology, as well as use of biomarkers are changing the way that pancreas cancer is diagnosed and staged. Although progress in treatment for pancreas cancer has been incremental, development of combination therapies involving both chemotherapeutic and biologic agents is ongoing.
Cancer is an evolutionary disease, containing the hallmarks of an asexually reproducing unicellular organism subject to evolutionary paradigms. Pancreatic ductal adenocarcinoma (PDAC) is a particularly robust example of this phenomenon. Genomic features indicate that pancreatic cancer cells are selected for fitness advantages when encountering the geographic and resource-depleted constraints of the microenvironment. Phenotypic adaptations to these pressures help disseminated cells to survive in secondary sites, a major clinical problem for patients with this disease.
The immune system varies in cell types, states, and locations. The complex networks, interactions, and responses of immune cells produce diverse cellular ecosystems composed of multiple cell types, accompanied by genetic diversity in antigen receptors. Within this ecosystem, innate and adaptive immune cells maintain and protect tissue function, integrity, and homeostasis upon changes in functional demands and diverse insults. Characterizing this inherent complexity requires studies at single-cell resolution. Recent advances such as massively parallel single-cell RNA sequencing and sophisticated computational methods are catalyzing a revolution in our understanding of immunology.
PDAC is the most common type of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis. In the present study to comprehensively delineate the PDAC intra-tumoral heterogeneity and the underlying mechanism for PDAC progression, single-cell RNA-seq (scRNA-seq) was employed to acquire the transcriptomic atlas of 57,530 individual pancreatic cells from primary PDAC tumors and control pancreases. The diverse malignant and stromal cell types, including two ductal subtypes with abnormal and malignant gene expression profiles respectively, were identified in PDAC.
The researchers found that the heterogenous malignant subtype was composed of several subpopulations with differential proliferative and migratory potentials. Cell trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. Furthermore, it was found a subset of ductal cells with unique proliferative features were associated with an inactivation state in tumor-infiltrating T cells, providing novel markers for the prediction of antitumor immune response. Together, the findings provided a valuable resource for deciphering the intra-tumoral heterogeneity in PDAC and uncover a connection between tumor intrinsic transcriptional state and T cell activation, suggesting potential biomarkers for anticancer treatment such as targeted therapy and immunotherapy.
First Cost-Effectiveness Study of Multi-Gene Panel Sequencing in Advanced Non-Small Cell Lung Cancer Shows Moderate Cost-Effectiveness, Exposes Crucial Practice Gap
WASHINGTON (June 27, 2019) — The results of the first economic modeling study to estimate the cost-effectiveness of “multi-gene panel sequencing” (MGPS) as compared to standard-of-care, single-gene tests for patients with advanced non-small cell lung cancer (aNSCLC) show that the MGPS tests are moderately cost-effective but could deliver more value if patients with test results identifying actionable genetic mutations consistently received genetically guided treatments. The results of the study, which was commissioned by the Personalized Medicine Coalition (PMC), underline the need to align clinical practices with an era of personalized medicine in which physicians can use diagnostic tests to identify specific biological markers that inform targeted prevention and treatment plans.
The study, which was published yesterday in JCO Clinical Cancer Informatics, analyzed the clinical and economic value of using MGPS testing to identify patients with tumors that over-express genetic mutations that could be targeted by available therapies designed to inhibit the function of those genes — a mainstay of modern care for aNSCLC patients. Using data provided by Flatiron Health, researchers examined clinical and cost information associated with the care of 5,688 patients with aNSCLC treated between 2011 – 2016, separating them into cohorts who received MGPS tests that assess at least 30 genetic mutations at once and those who received only “single-marker genetic testing” (SMGT) of less than 30 genes.
Compared to SMGT, the MGPS testing strategy, including downstream treatment and monitoring of disease, incurred costs equal to $148,478 for each year of life that it facilitated, a level suggesting that MGPS is moderately cost-effective compared to commonly cited thresholds in the U.S., which range from $50,000 to $200,000 per life year (LY) gained.
The authors of the study point out, however, that physicians only prescribed a targeted therapy to some of the patients whose MGPS test results revealed actionable mutations. MGPS tests can only improve downstream patient outcomes if actionable results are used to put the patient on a targeted treatment regimen that is more effective than the therapy they would otherwise have been prescribed. It is therefore impossible for the cost of an MGPS test to translate into additional LYs if actionable results do not result in the selection of a targeted treatment regimen.
Although MGPS testing revealed actionable mutations in 30.1 percent of the patients in the study cohort, only 21.4 percent of patients who underwent MGPS testing received a targeted treatment.
The study’s authors calculated that if all MGPS-tested patients with actionable mutations had received a targeted therapy, MGPS testing would deliver measurably better value ($110,000 per LY gained).
“This research underlines the importance of ensuring that clinical practices keep pace with scientific progress in personalized medicine so that we can maximize the benefits of diagnostic tests that can improve patient care and make the health system more efficient by ensuring that safe and effective targeted therapies are prescribed to those patients who will benefit,” said PMC President Edward Abrahams.
The study’s authors include Dr. Lotte Steuten, Vice President and Head of Consulting, The Office of Health Economics, London, U.K., and Affiliate Associate Faculty Member, Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center; Dr. Bernardo Goulart, Associate Faculty Member, Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center; Dr. Neal Meropol, Vice President, Research Oncology, Flatiron Health; Dr. Daryl Pritchard, Senior Vice President, Science Policy, Personalized Medicine Coalition; and Dr. Scott Ramsey, Director, Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center.
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About the Personalized Medicine Coalition:
The Personalized Medicine Coalition, representing innovators, scientists, patients, providers and payers, promotes the understanding and adoption of personalized medicine concepts, services and products to benefit patients and the health system. For more information, please visit www.personalizedmedicinecoalition.org.
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.
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.
eProceedings for BIO 2019 International Convention, June 3-6, 2019 Philadelphia Convention Center; Philadelphia PA, Real Time Coverage by Stephen J. Williams, PhD @StephenJWillia2
CONFERENCE OVERVIEW
Real Time Coverage of BIO 2019 International Convention, June 3-6, 2019 Philadelphia Convention Center; Philadelphia PA
Reporter: Stephen J. Williams, PhD @StephenJWillia2
Real Time Coverage @BIOConvention #BIO2019: Machine Learning and Artificial Intelligence: Realizing Precision Medicine One Patient at a Time, 6/5/2019, Philadelphia PA
Real Time @BIOConvention #BIO2019:#Bitcoin Your Data! From Trusted Pharma Silos to Trustless Community-Owned Blockchain-Based Precision Medicine Data Trials, 6/5/2019, Philadelphia PA
Real Time Coverage @BIOConvention #BIO2019: June 4 Morning Sessions; Global Biotech Investment & Public-Private Partnerships, 6/4/2019, Philadelphia PA
Real Time Coverage @BIOConvention #BIO2019: Understanding the Voices of Patients: Unique Perspectives on Healthcare; June 4, 2019, 11:00 AM, Philadelphia PA
Real Time Coverage @BIOConvention #BIO2019: Issues of Risk and Reproduceability in Translational and Academic Collaboration; 2:30-4:00 June 3, 2019, Philadelphia PA
Real Time Coverage @BIOConvention #BIO2019: After Trump’s Drug Pricing Blueprint: What Happens Next? A View from Washington; June 3, 2019 1:00 PM, Philadelphia PA
Hematologist and oncologist Siddhartha Mukherjee was born in New Delhi, India. He holds a BS in biology from Stanford University, a DPhil in immunology from Oxford University (where he was a Rhodes Scholar), and an MD from Harvard Medical School. He completed his internal medicine residency and an oncology fellowship at Massachusetts General Hospital. Dr. Murkherjee is an assistant professor of medicine at Columbia University Medical Center. He lives in Manhattan with his wife, artist Sarah Sze, and their two daughters. His Pulitzer Prize-winning book, The Emperor of All Maladies: A Biography of Cancer, tells the story of cancer from its first description in an ancient Egyptian scroll to the gleaming laboratories of modern research institutions. A three-part documentary series based on the book, directed by Barak Goodman and executive produced by Ken Burns, debuts on PBS stations March 30 and continues on March 31 and April 1. The film interweaves a sweeping historical narrative with intimate stories about contemporary patients and an investigation into the latest scientific breakthroughs. He has also written the award winning book “The Gene: An Intimate History” and is Founder of Vor Biopharma, who had just published on their CD33 engineered hematopoetic stem cells as an immunooncology therapy VOR33.
Hon. James C. Greenwood- former Congressional representative and Founder CEO of BIO: moderator
Greenwood: Never have the threats from DC to innovation in the biotech field been so great. Focused on some great recent innovations and successes in gene therapy. Although the cost high, father of two LMR retinopathy patients said if his sons had to go through a lifetime of constant care it would cost much more than the gene therapy from Spark cost. Politicians need to realize that medicines that completely cure diseases are worth much more. They should meet in the middle with respect to developing a new payer model that will not hurt innovation.
Dr. Mukherjee: He go into oncology from a virology PhD because he liked to understand the human aspect
of disease. As an oncologist he gets to interact more closely with patients. The oncology horizon is always changing. He likened his view of oncology and cancer as a pyramid with prevention the base, then early detection then therapy at top.
We haven’t found preventable human carcinogens, none that is highly proven causal
This will be the next challenge for cancer researchers, to figure out why we can’t identify these preventable carcinogens.
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