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Google’s Artificial Intelligence Algorithm Shows Improved Accuracy in Reading Mammograms

Posted in Artificial Intelligence - General, Artificial Intelligence Applications in Health Care, Artificial Intelligence in CANCER, Artificial Intelligence in Health Care - Tools & Innovations, Artificial Intelligence in Medicine - Application for Diagnosis, Breast Cancer - impalpable breast lesions, Cancer - General, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Screening, Deep Learning in Pathology, tagged , , , , , , , , , on January 2, 2020| Leave a Comment »


Google AI improves accuracy of reading mammograms, study finds

Anne Stych, Staff Writer
Jan 2, 2020, 10:28am EST

Google AI improves accuracy of reading mammograms, study finds

Weinberg-Clark Photography

Google CFO Ruth Porat has blogged about twice battling breast cancer.

Artificial intelligence was often more accurate than radiologists in detecting breast cancer from mammograms in a study conducted by researchers using Google AI technology.

The study, published in the journal Nature, used mammograms from approximately 90,000 women in which the outcomes were known to train technology from Alphabet Inc’s DeepMind AI unit, now part of Google Health, Yahoo news reported.

The AI system was then used to analyze images from 28,000 other women and often diagnosed early cancers more accurately than the radiologists who originally interpreted the mammograms.

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In another test, AI outperformed six radiologists in reading 500 mammograms. However, while the AI system found cancers the humans missed, it also failed to find cancers flagged by all six radiologists, reports The New York Times.

The researchers said the study “paves the way” for further clinical trials.

Writing in Nature, Etta D. Pisano, chief research officer at the American College of Radiology and professor in residence at Harvard Medical School, noted, “The real world is more complicated and potentially more diverse than the type of controlled research environment reported in this study.”

Ruth Porat, senior vice president and chief financial officer Alphabet, Inc., wrote in a company blog titled “Breast cancer and tech…a reason for optimism” in October about twice battling the disease herself, and the importance of her company’s application of AI to healthcare innovations.

She said that focus had already led to the development of a deep learning algorithm to help pathologists assess tissue associated with metastatic breast cancer.

“By pinpointing the location of the cancer more accurately, quickly and at a lower cost, care providers might be able to deliver better treatment for more patients,” she wrote.

Google also has created algorithms that help medical professionals diagnose lung cancer, and eye disease in people with diabetes, per the Times.

Porat acknowledged that Google’s research showed the best results occur when medical professionals and technology work together.

Any insights provided by AI must be “paired with human intelligence and placed in the hands of skilled researchers, surgeons, oncologists, radiologists and others,” she said.

Anne Stych is a staff writer for Bizwomen.
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Medicine in 2045 – Perspectives by World Thought Leaders in the Life Sciences & Medicine

Posted in Advanced Computing Platform, AI, Big Data, BioBanking, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Cancer and Current Therapeutics, CAST - Alternative to CRISPR/Cas9, Computational Biology/Systems and Bioinformatics, CRISPR/Cas9 & Gene Editing, Diagnostic Immunology, Digital HealthCare – biotech & internet joint ventures, Disease Biology, DNA repair, Drug Delivery Platform Technology, Gene Editing Impact on Longevity, Genetics & Innovations in Treatment, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Care System by Country, Health Economics and Outcomes Research, HealthCare IT, Human Immune System in Health and in Disease, Immuno-Oncology & Genomics, Immunodiagnostics, Liquid Biopsy: Circulating Tumor Cells in Urine and Blood, Microfuidics, Single Cell Genomics, Variation in human protein-coding regions on December 9, 2019| Leave a Comment »


Medicine in 2045 – Perspectives by World Thought Leaders in the Life Sciences & Medicine

Reporter: Aviva Lev-Ari, PhD, RN

 

This report is based on an article in Nature Medicine | VOL 25 | December 2019 | 1800–1809 | http://www.nature.com/naturemedicine

Looking forward 25 years: the future of medicine.

Nat Med 25, 1804–1807 (2019) doi:10.1038/s41591-019-0693-y

 

Aviv Regev, PhD

Core member and chair of the faculty, Broad Institute of MIT and Harvard; director, Klarman Cell Observatory, Broad Institute of MIT and Harvard; professor of biology, MIT; investigator, Howard Hughes Medical Institute; founding co-chair, Human Cell Atlas.

  • millions of genome variants, tens of thousands of disease-associated genes, thousands of cell types and an almost unimaginable number of ways they can combine, we had to approximate a best starting point—choose one target, guess the cell, simplify the experiment.
  • In 2020, advances in polygenic risk scores, in understanding the cell and modules of action of genes through genome-wide association studies (GWAS), and in predicting the impact of combinations of interventions.
  • we need algorithms to make better computational predictions of experiments we have never performed in the lab or in clinical trials.
  • Human Cell Atlas and the International Common Disease Alliance—and in new experimental platforms: data platforms and algorithms. But we also need a broader ecosystem of partnerships in medicine that engages interaction between clinical experts and mathematicians, computer scientists and engineers

Feng Zhang, PhD

investigator, Howard Hughes Medical Institute; core member, Broad Institute of MIT and Harvard; James and Patricia Poitras Professor of Neuroscience, McGovern Institute for Brain Research, MIT.

  • fundamental shift in medicine away from treating symptoms of disease and toward treating disease at its genetic roots.
  • Gene therapy with clinical feasibility, improved delivery methods and the development of robust molecular technologies for gene editing in human cells, affordable genome sequencing has accelerated our ability to identify the genetic causes of disease.
  • 1,000 clinical trials testing gene therapies are ongoing, and the pace of clinical development is likely to accelerate.
  • refine molecular technologies for gene editing, to push our understanding of gene function in health and disease forward, and to engage with all members of society

Elizabeth Jaffee, PhD

Dana and Albert “Cubby” Broccoli Professor of Oncology, Johns Hopkins School of Medicine; deputy director, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

  • a single blood test could inform individuals of the diseases they are at risk of (diabetes, cancer, heart disease, etc.) and that safe interventions will be available.
  • developing cancer vaccines. Vaccines targeting the causative agents of cervical and hepatocellular cancers have already proven to be effective. With these technologies and the wealth of data that will become available as precision medicine becomes more routine, new discoveries identifying the earliest genetic and inflammatory changes occurring within a cell as it transitions into a pre-cancer can be expected. With these discoveries, the opportunities to develop vaccine approaches preventing cancers development will grow.

Jeremy Farrar, OBE FRCP FRS FMedSci

Director, Wellcome Trust.

  • shape how the culture of research will develop over the next 25 years, a culture that cares more about what is achieved than how it is achieved.
  • building a creative, inclusive and open research culture will unleash greater discoveries with greater impact.

John Nkengasong, PhD

Director, Africa Centres for Disease Control and Prevention.

  • To meet its health challenges by 2050, the continent will have to be innovative in order to leapfrog toward solutions in public health.
  • Precision medicine will need to take center stage in a new public health order— whereby a more precise and targeted approach to screening, diagnosis, treatment and, potentially, cure is based on each patient’s unique genetic and biologic make-up.

Eric Topol, MD

Executive vice-president, Scripps Research Institute; founder and director, Scripps Research Translational Institute.

  • In 2045, a planetary health infrastructure based on deep, longitudinal, multimodal human data, ideally collected from and accessible to as many as possible of the 9+ billion people projected to then inhabit the Earth.
  • enhanced capabilities to perform functions that are not feasible now.
  • AI machines’ ability to ingest and process biomedical text at scale—such as the corpus of the up-to-date medical literature—will be used routinely by physicians and patients.
  • the concept of a learning health system will be redefined by AI.

Linda Partridge, PhD

Professor, Max Planck Institute for Biology of Ageing.

  • Geroprotective drugs, which target the underlying molecular mechanisms of ageing, are coming over the scientific and clinical horizons, and may help to prevent the most intractable age-related disease, dementia.

Trevor Mundel, MD

President of Global Health, Bill & Melinda Gates Foundation.

  • finding new ways to share clinical data that are as open as possible and as closed as necessary.
  • moving beyond drug donations toward a new era of corporate social responsibility that encourages biotechnology and pharmaceutical companies to offer their best minds and their most promising platforms.
  • working with governments and multilateral organizations much earlier in the product life cycle to finance the introduction of new interventions and to ensure the sustainable development of the health systems that will deliver them.
  • deliver on the promise of global health equity.

Josep Tabernero, MD, PhD

Vall d’Hebron Institute of Oncology (VHIO); president, European Society for Medical Oncology (2018–2019).

  • genomic-driven analysis will continue to broaden the impact of personalized medicine in healthcare globally.
  • Precision medicine will continue to deliver its new paradigm in cancer care and reach more patients.
  • Immunotherapy will deliver on its promise to dismantle cancer’s armory across tumor types.
  • AI will help guide the development of individually matched
  • genetic patient screenings
  • the promise of liquid biopsy policing of disease?

Pardis Sabeti, PhD

Professor, Harvard University & Harvard T.H. Chan School of Public Health and Broad Institute of MIT and Harvard; investigator, Howard Hughes Medical Institute.

  • the development and integration of tools into an early-warning system embedded into healthcare systems around the world could revolutionize infectious disease detection and response.
  • But this will only happen with a commitment from the global community.

Els Toreele, PhD

Executive director, Médecins Sans Frontières Access Campaign

  • we need a paradigm shift such that medicines are no longer lucrative market commodities but are global public health goods—available to all those who need them.
  • This will require members of the scientific community to go beyond their role as researchers and actively engage in R&D policy reform mandating health research in the public interest and ensuring that the results of their work benefit many more people.
  • The global research community can lead the way toward public-interest driven health innovation, by undertaking collaborative open science and piloting not-for-profit R&D strategies that positively impact people’s lives globally.

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New Mutant KRAS Inhibitors Are Showing Promise in Cancer Clinical Trials: Hope For the Once ‘Undruggable’ Target

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, interventional oncology, KRAS Mutation, Pancreatic cancer, tagged , , , , , , , , , , on November 11, 2019| Leave a Comment »


New Mutant KRAS Inhibitors Are Showing Promise in Cancer Clinical Trials: Hope For the Once ‘Undruggable’ Target

Curator: Stephen J. Williams, Ph.D.

The November 1st issue of Science highlights a series of findings which give cancer researchers some hope in finally winning a thirty year war with the discovery of drugs that target KRAS, one of the most commonly mutated oncogenes  (25% of cancers), and thought to be a major driver of tumorigenesis. Once considered an undruggable target, mainly because of the smooth surface with no obvious pockets to fit a drug in, as well as the plethora of failed attempts to develop such an inhibitor, new findings with recently developed candidates, highlighted in this article and other curated within, are finally giving hope to researchers and oncologists who have been hoping for a clinically successful inhibitor of this once considered elusive target.

 

For a great review on development of G12C KRas inhibitors please see Dr. Hobb’s and Channing Der’s review in Cell Selective Targeting of the KRAS G12C Mutant: Kicking KRAS When It’s Down

Figure 1Mechanism of Action of ARS853 showing that the inhibitors may not need bind to the active conformation of KRAS for efficacy

Abstract: Two recent studies evaluated a small molecule that specifically binds to and inactivates the KRAS G12C mutant. The new findings argue that the perception that mutant KRAS is persistently frozen in its active GTP-bound form may not be accurate.

 

Although the development of the KRASG12C-specific inhibitor, compound 12 (Ostrem et al., 2013), was groundbreaking, subsequent studies found that the potency of compound 12 in cellular assays was limited (Lito et al., 2016, Patricelli et al., 2016). A search for more-effective analogs led to the development of ARS853 (Patricelli et al., 2016), which exhibited a 600-fold increase of its reaction rate in vitro over compound 12 and cellular activities in the low micromolar range.

 

A Summary and more in-depth curation of the Science article is given below:

After decades, progress against an ‘undruggable’ cancer target

Summary

Cancer researchers are making progress toward a goal that has eluded them for more than 30 years: shrinking tumors by shutting off a protein called KRAS that drives growth in many cancer types. A new type of drug aimed at KRAS made tumors disappear in mice and shrank tumors in lung cancer patients, two companies report in papers published this week. It’s not yet clear whether the drugs will extend patients’ lives, but the results are generating a wave of excitement. And one company, Amgen, reports an unexpected bonus: Its drug also appears to stimulate the immune system to attack tumors, suggesting it could be even more powerful if paired with widely available immunotherapy treatments.

Jocelyn Kaiser. After decades, progress against an ‘undruggable’ cancer target. Science  01 Nov 2019: Vol. 366, Issue 6465, pp. 561 DOI: 10.1126/science.366.6465.561

The article highlights the development of three inhibitors: by Wellspring Biosciences, Amgen, and Mirati Therapeutics.

Wellspring BioSciences

 

In 2013, Dr. Kevan Shokat’s lab at UCSF discovered a small molecule that could fit in the groove of the KRAS mutant G12C.  The G12C as well as the G12D is a common mutation found in KRAS in cancers. KRAS p.G12C mutations predominate in NSCLC comprising 11%–16% of lung adenocarcinomas (45%–50% of mutant KRAS is p.G12C) (Campbell et al., 2016; Jordan et al., 2017), as well as 1%–4% of pancreatic and colorectal adenocarcinomas, respectively (Bailey et al., 2016; Giannakis et al., 2016).  This inhibitor was effective in shrinking, in mouse studies conducted by Wellspring Biosciences,  implanted tumors containing this mutant KRAS.

 

See Wellspring’s news releases below:

March, 2016 – Publication – Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State

February, 2016 – Publication – Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism

Amgen

 

Amgen press release on AMG510 Clinical Trial at ASCO 2019

 

THOUSAND OAKS, Calif., June 3, 2019 /PRNewswire/ — Amgen (NASDAQ: AMGN) today announced the first clinical results from a Phase 1 study evaluating investigational AMG 510, the first KRASG12C inhibitor to reach the clinical stage. In the trial, there were no dose-limiting toxicities at tested dose levels. AMG 510 showed anti-tumor activity when administered as a monotherapy in patients with locally-advanced or metastatic KRASG12C mutant solid tumors. These data are being presented during an oral session at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

“KRAS has been a target of active exploration in cancer research since it was identified as one of the first oncogenes more than 30 years ago, but it remained undruggable due to a lack of traditional small molecule binding pockets on the protein. AMG 510 seeks to crack the KRAS code by exploiting a previously hidden groove on the protein surface,” said David M. Reese, M.D., executive vice president of Research and Development at Amgen. “By irreversibly binding to cysteine 12 on the mutated KRAS protein, AMG 510 is designed to lock it into an inactive state. With high selectivity for KRASG12C, we believe investigational AMG 510 has high potential as both a monotherapy and in combination with other targeted and immune therapies.”

The Phase 1, first-in-human, open-label multicenter study enrolled 35 patients with various tumor types (14 non-small cell lung cancer [NSCLC], 19 colorectal cancer [CRC] and two other). Eligible patients were heavily pretreated with at least two or more prior lines of treatment, consistent with their tumor type and stage of disease. 

Canon, J., Rex, K., Saiki, A.Y. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019) doi:10.1038/s41586-019-1694-1

Besides blocking tumor growth, AMG510 appears to stimulate T cells to attack the tumor, thus potentially supplying a two pronged attack to the tumor, inhibiting oncogenic RAS and stimulating anti-tumor immunity.

 

Mirati Therapeutics

 

Mirati’s G12C KRAS inhibitor (MRTX849) is being investigated in a variety of solid malignancies containing the KRAS mutation.

 

For recent publication on results in lung cancer see Patricelli M.P., et al. Cancer Discov. 2016; (Published online January 6, 2016)

For more information on Mirati’s KRAS G12C inhibitor see https://www.mirati.com/pipeline/kras-g12c/

 

KRAS G12C Inhibitor (MRTX849)

Study 849-001 – Phase 1b/2 of single agent MRTX849 for solid tumors with KRAS G12C mutation

Phase 1b/2 clinical trial of single agent MRTX849 in patients with advanced solid tumors that have a KRAS G12C mutation.

See details for this study at clinicaltrials.gov

 

Additional References:

Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism.

Lito P et al. Science. (2016)

Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

Janes MR et al. Cell. (2018)

Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C.

Zeng M et al. Cell Chem Biol. (2017)

Campbell, J.D., Alexandrov, A., Kim, J., Wala, J., Berger, A.H., Pedamallu, C.S., Shukla, S.A., Guo, G., Brooks, A.N., Murray, B.A., et al.; Cancer Genome Atlas Research Network (2016). Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat. Genet.48, 607–616

Jordan, E.J., Kim, H.R., Arcila, M.E., Barron, D., Chakravarty, D., Gao, J., Chang, M.T., Ni, A., Kundra, R., Jonsson, P., et al. (2017). Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7, 596–609.

Bailey, P., Chang, D.K., Nones, K., Johns, A.L., Patch, A.M., Gingras, M.C., Miller, D.K., Christ, A.N., Bruxner, T.J., Quinn, M.C., et al.; Australian Pancreatic Cancer Genome Initiative (2016). Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52.

Giannakis, M., Mu, X.J., Shukla, S.A., Qian, Z.R., Cohen, O., Nishihara, R., Bahl, S., Cao, Y., Amin-Mansour, A., Yamauchi, M., et al. (2016). Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 15, 857–865.

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Real Time Coverage @BIOConvention #BIO2019: Gene Therapy 2.0: No Longer Science Fiction 1:00-2:15 pm June 3 Philadelphia PA

Posted in Cancer - General, Cancer and Current Therapeutics, Drug Delivery Platform Technology, Gene Therapy & Gene Editing Development, Genetics & Innovations in Treatment, Innovations, Neurological Diseases, Pharmaceutical Drug Discovery, Scientific & Biotech Conferences: Press Coverage, tagged , , , , , , , , on October 15, 2019| Leave a Comment »


Real Time Coverage @BIOConvention #BIO2019: Gene Therapy 2.0: No Longer Science Fiction 1:00-2:15 pm June 3 Philadelphia PA

Reporter: Stephen J. Williams Ph.D. @StephenJWillia2

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Other Articles on Gene Therapy on this Open Access Journal Include:

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Efficiency of PARP inhibitors beyond BRCA mutations

Posted in Cancer - General, Cancer and Current Therapeutics, tagged , , , , on July 25, 2019| 1 Comment »


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.

SOURCE

PARP inhibitors sometimes work beyond BRCA-mutations, researchers may finally know why

Other related articles published in this Open Access Online Scientific Journal include the following:

Targeting PARP

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/05/19/targeting-parp/

 

 

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An Intelligent DNA Nanorobot to Fight Cancer by Targeting HER2 Expression

Posted in Apoptosis, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biological Networks, Breast Cancer - impalpable breast lesions, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, cancer metabolism, Cancer Prevention: Research & Programs, Cancer Screening, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cancer-Immune Interactions, Cell Biology, Cell Biology, Signaling & Cell Circuits, Metabolic Immuno-Oncology, Monoclonal Immunotherapy, Oligonucleotide Therapeutics & Delivery, Precision Cancer Medicine, RNA Biology, Cancer and Therapeutics, Signaling & Cell Circuits, tagged , , , , , , on July 24, 2019| Leave a Comment »


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.

 

References:

 

https://pubs.acs.org/doi/10.1021/acs.nanolett.9b01320

 

https://www.ncbi.nlm.nih.gov/pubmed/27939064

 

https://www.ncbi.nlm.nih.gov/pubmed/11694782

 

https://www.ncbi.nlm.nih.gov/pubmed/27082923

 

https://www.ncbi.nlm.nih.gov/pubmed/25365825

 

https://www.ncbi.nlm.nih.gov/pubmed/26840503

 

https://www.ncbi.nlm.nih.gov/pubmed/29802035

 

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Single-cell RNA-seq helps in finding intra-tumoral heterogeneity in pancreatic cancer

Posted in Artificial Intelligence in CANCER, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biological Networks, Biological Networks, Gene Regulation and Evolution, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Informatics, Cancer Prevention: Research & Programs, Cancer Screening, Cancer-Immune Interactions, Cell Biology, Cell Biology, Signaling & Cell Circuits, Immuno-Oncology & Genomics, Meta-analysis of transcriptome data, mRNA platform in Drug DIscovery, Pancreatic adenocarcinoma classifier, Pancreatic cancer, Precision Cancer Medicine, RNA Biology, RNA Biology, Cancer and Therapeutics, Single-cell sequencing, Transcriptomics, tagged , , , , on July 21, 2019| Leave a Comment »


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.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/31273297

 

https://www.ncbi.nlm.nih.gov/pubmed/21491194

 

https://www.ncbi.nlm.nih.gov/pubmed/27444064

 

https://www.ncbi.nlm.nih.gov/pubmed/28983043

 

https://www.ncbi.nlm.nih.gov/pubmed/24976721

 

https://www.ncbi.nlm.nih.gov/pubmed/27693023

 

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