Feeds:
Posts
Comments

Archive for the ‘Cancer Screening’ Category


Happy 80th Birthday: Radioiodine (RAI) Theranostics: Collaboration between Physics and Medicine, the Utilization of Radionuclides to Diagnose and Treat: Radiation Dosimetry by Discoverer Dr. Saul Hertz, the early history of RAI in diagnosing and treating Thyroid diseases and Theranostics

 

Guest Author: Barbara Hertz

 203-661-0777

htziev@aol.com

Celebrating eighty years of radionuclide therapy and the work of Saul Hertz

First published: 03 February 2021

Both authors contributed to the development, drafting and final editing of this manuscript and are responsible for its content.

Abstract

March 2021 will mark the eightieth anniversary of targeted radionuclide therapy, recognizing the first use of radioactive iodine to treat thyroid disease by Dr. Saul Hertz on March 31, 1941. The breakthrough of Dr. Hertz and collaborator physicist Arthur Roberts was made possible by rapid developments in the fields of physics and medicine in the early twentieth century. Although diseases of the thyroid gland had been described for centuries, the role of iodine in thyroid physiology had been elucidated only in the prior few decades. After the discovery of radioactivity by Henri Becquerel in 1897, rapid advancements in the field, including artificial production of radioactive isotopes, were made in the subsequent decades. Finally, the diagnostic and therapeutic use of radioactive iodine was based on the tracer principal that was developed by George de Hevesy. In the context of these advancements, Hertz was able to conceive the potential of using of radioactive iodine to treat thyroid diseases. Working with Dr. Roberts, he obtained the experimental data and implemented it in the clinical setting. Radioiodine therapy continues to be a mainstay of therapy for hyperthyroidism and thyroid cancer. However, Hertz struggled to gain recognition for his accomplishments and to continue his work and, with his early death in 1950, his contributions have often been overlooked until recently. The work of Hertz and others provided a foundation for the introduction of other radionuclide therapies and for the development of the concept of theranostics.

SOURCE

https://aapm.onlinelibrary.wiley.com/doi/full/10.1002/acm2.13175

 

 

SOURCE

https://www.youtube.com/watch?v=34Qhm8CeMuc

 

http://www.wjnm.org/article.asp?issn=1450-1147;year=…

http://www.wjnm.org/text.asp?2019/18/1/8/250309

Abstract

Dr. Saul Hertz was Director of The Massachusetts General Hospital’s Thyroid Unit, when he heard about the development of artificial radioactivity. He conceived and brought from bench to bedside the successful use of radioiodine (RAI) to diagnose and treat thyroid diseases. Thus was born the science of theragnostics used today for neuroendocrine tumors and prostate cancer. Dr. Hertz’s work set the foundation of targeted precision medicine.

Keywords: Dr. Saul Hertz, nuclear medicine, radioiodine

 

How to cite this article:
Hertz B. A tribute to Dr. Saul Hertz: The discovery of the medical uses of radioiodine. World J Nucl Med 2019;18:8-12

 

How to cite this URL:
Hertz B. A tribute to Dr. Saul Hertz: The discovery of the medical uses of radioiodine. World J Nucl Med [serial online] 2019 [cited 2021 Mar 2];18:8-12. Available from: http://www.wjnm.org/text.asp?2019/18/1/8/250309

 

 

  • Dr Saul Hertz (1905-1950) discovers the medical uses of radioiodine

Barbara Hertz, Pushan Bharadwaj, Bennett Greenspan»

Abstract » PDF» doi: 10.24911/PJNMed.175-1582813482

 

SOURCE

http://saulhertzmd.com/home

 

  • Happy 80th Birthday: Radioiodine (RAI) Theranostics

Thyroid practitioners and patients are acutely aware of the enormous benefit nuclear medicine has made to mankind. This month we celebrate the 80th anniversary of the early use of radioiodine(RAI).

Dr. Saul Hertz predicted that radionuclides “…would hold the key to the larger problem of cancer in general,” and may just be the best hope for diagnosing and treating cancer successfully.  Yes, RAI has been used for decades to diagnose and treat disease.  Today’s “theranostics,” a term that is a combination of “therapy” and “diagnosis” is utilized in the treatment of thyroid disease and cancer. 

            This short note is to celebrate Dr. Saul Hertz who conceived and brought from bench to bedside the medical uses of RAI; then in the form of 25 minute iodine-128.  

On March 31st 1941, Massachusetts General Hospital’s Dr. Saul Hertz (1905-1950) administered the first therapeutic use of Massachusetts Institute of Technology (MIT) cyclotron produced RAI.  This landmark case was the first in Hertz’s clinical studies conducted with MIT, physicist Arthur Roberts, Ph.D.

[Photo – Courtesy of Dr Saul Hertz Archives ]

Dr Saul Hertz demonstrating RAI Uptake Testing

            Dr. Hertz’s research and successful utilization of radionuclides to diagnose and treat diseases and conditions, established the use of radiation dosimetry and the collaboration between physics and medicine and other significant practices.   Sadly, Saul Hertz (a WWII veteran) died at a very young age.  

 

About Dr. Saul Hertz

Dr. Saul Hertz (1905 – 1950) discovered the medical uses of radionuclides.  His breakthrough work with radioactive iodine (RAI) created a dynamic paradigym change integrating the sciences.  Radioactive iodine (RAI) is the first and Gold Standard of targeted cancer therapies.  Saul Hertz’s research documents Hertz as the first and foremost person to conceive and develop the experimental data on RAI and apply it in the clinical setting.

Dr. Hertz was born to Orthodox Jewish immigrant parents in Cleveland, Ohio on April 20, 1905. He received his A.B. from the University of Michigan in 1925 with Phi Beta Kappa honors. He graduated from Harvard Medical School in 1929 at a time of quotas for outsiders. He fulfilled his internship and residency at Mt. Sinai Hospital in Cleveland. He came back to Boston in 1931 as a volunteer to join The Massachusetts General Hospital serving as the Chief of the Thyroid Unit from 1931 – 1943.

Two years after the discovery of artifically radioactivity, on November 12, 1936 Dr. Karl Compton, president of the Massachusetts Institute of Technology (MIT), spoke at Harvard Medical School.  President Compton’s topic was What Physics can do for Biology and Medicine. After the presentation Dr. Hertz spontaneously asked Dr. Compton this seminal question, “Could iodine be made radioactive artificially?” Dr. Compton responded in writing on December 15, 1936 that in fact “iodine can be made artificially radioactive.”

Shortly thereafter, a collaboration between Dr. Hertz (MGH) and Dr. Arthur Roberts, a physicist of MIT, was established. In late 1937, Hertz and Roberts created and produced animal studies  involving 48 rabbits that demonstrated that the normal thyroid gland concentrated Iodine 128 (non cyclotron produced), and the hyperplastic thyroid gland took up even more Iodine.  This was a GIANT step for Nuclear Medicine.

In early 1941, Dr. Hertz administer the first therapeutic treatment of MIT Markle Cyclotron produced radioactive iodine (RAI) at the Massachusetts General Hospital.  This  led to the first series of twenty-nine patients with hyperthyroidism being treated successfully with RAI. ( see “Research” RADIOACTIVE IODINE IN THE STUDY OF THYROID PHYSIOLOGY VII The use of Radioactive Iodine Therapy in Hyperthyroidism, Saul Hertz and Arthur Roberts, JAMA Vol. 31 Number 2).

In 1937, at the time of the rabbit studies Dr Hertz conceived of RAI in therapeutic treatment of thyroid carsonoma.  In 1942 Dr Hertz gave clinical trials of RAI to patients with thyroid carcinoma.

After serving in the Navy during World War II, Dr. Hertz wrote to the director of the Mass General Hospital in Boston, Dr. Paxon on March 12, 1946, “it is a coincidence that my new research project is in Cancer of the Thyroid, which I believe holds the key to the larger problem of cancer in general.”

Dr. Hertz established the Radioactive Isotope Research Institute, in September, 1946 with a major focus on the use of fission products for the treatment of thyroid cancer, goiter, and other malignant tumors. Dr Samuel Seidlin was the Associate Director and managed the New York City facilities. Hertz also researched the influence of hormones on cancer.

Dr. Hertz’s use of radioactive iodine as a tracer in the diagnostic process, as a treatment for Graves’ disease and in the treatment of cancer of the thyroid remain preferred practices. Saul Hertz is the Father of Theranostics.

Saul Hertz passed at 45 years old from a sudden death heart attack as documented by an autopsy. He leaves an enduring legacy impacting countless generations of patients, numerous institutions worldwide and setting the cornerstone for the field of Nuclear Medicine. A cancer survivor emailed, The cure delivered on the wings of prayer was Dr Saul Hertz’s discovery, the miracle of radioactive iodine. Few can equal such a powerful and precious gift. 

To read and hear more about Dr. Hertz and the early history of RAI in diagnosing and treating thyroid diseases and theranostics see –

http://saulhertzmd.com/home

 

   References in https://www.wjnm.org/article.asp?issn=1450-1147;year=2019;volume=18;issue=1;spage=8;epage=12;aulast=Hertz

 

Top

 

1.
Hertz S, Roberts A. Radioactive iodine in the study of thyroid physiology. VII The use of radioactive iodine therapy in hyperthyroidism. J Am Med Assoc 1946;131:81-6.  Back to cited text no. 1
2.
Hertz S. A plan for analysis of the biologic factors involved in experimental carcinogenesis of the thyroid by means of radioactive isotopes. Bull New Engl Med Cent 1946;8:220-4.  Back to cited text no. 2
3.
Thrall J. The Story of Saul Hertz, Radioiodine and the Origins of Nuclear Medicine. Available from: http://www.youtube.com/watch?v=34Qhm8CeMuc. [Last accessed on 2018 Dec 01].  Back to cited text no. 3
4.
Braverman L. 131 Iodine Therapy: A Brief History. Available from: http://www.am2016.aace.com/presentations/friday/F12/hertz_braverman.pdf. [Last accessed on 2018 Dec 01].  Back to cited text no. 4
5.
Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): A single-centre, single-arm, phase 2 study. Lancet Oncol 2018;19:825-33.  Back to cited text no. 5
6.
Krolicki L, Morgenstern A, Kunikowska J, Koiziar H, Krolicki B, Jackaniski M, et al. Glioma Tumors Grade II/III-Local Alpha Emitters Targeted Therapy with 213 Bi-DOTA-Substance P, Endocrine Abstracts. Vol. 57. Society of Nuclear Medicine and Molecular Imaging; 2016. p. 632.  Back to cited text no. 6
7.
Baum RP, Kulkarni HP. Duo PRRT of neuroendocrine tumours using concurrent and sequential administration of Y-90- and Lu-177-labeled somatostatin analogues. In: Hubalewska-Dydejczyk A, Signore A, de Jong M, Dierckx RA, Buscombe J, Van de Wiel CJ, editors. Somatostatin Analogues from Research to Clinical Practice. New York: Wiley; 2015.  Back to cited text no. 7

 

SOURCE

From: htziev@aol.com” <htziev@aol.com>

Reply-To: htziev@aol.com” <htziev@aol.com>

Date: Tuesday, March 2, 2021 at 11:04 AM

To: “Aviva Lev-Ari, PhD, RN” <AvivaLev-Ari@alum.berkeley.edu>

Subject: Dr Saul Hertz : Discovery for the Medical Uses of RADIOIODINE (RAI) MARCH 31ST: 80 Years

 

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

 

Experience with Thyroid Cancer

Author: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/11/23/my-experience-with-thyroid-cancer/

 

New Guidelines and Meeting Information on Advanced Thyroid Cancer as Reported by Cancer Network (Meeting Highlights)

Reporter: Stephen J. Williams, Ph.D.

https://pharmaceuticalintelligence.com/2015/10/20/new-guidelines-and-meeting-information-on-advanced-thyroid-cancer-as-reported-by-cancer-network-meeting-highlights/

The Experience of a Patient with Thyroid Cancer

Interviewer and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/14/the-experience-of-a-patient-with-thyroid-cancer/

 

Parathyroids and Bone Metabolism

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/02/10/parathyroids-and-bone-metabolism/

 

Thyroid Function and Disorders

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/02/05/thyroid-function-and-disorders/

Summary and Perspectives: Impairments in Pathological States: Endocrine Disorders, Stress Hypermetabolism and Cancer

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/11/09/summary-and-perspectives-impairments-in-pathological-states-endocrine-disorders-stress-hypermetabolism-cancer/

Introduction to Impairments in Pathological States: Endocrine Disorders, Stress Hypermetabolism and Cancer

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/11/08/introduction-to-impairments-in-pathological-states-endocrine-disorders-stress-hypermetabolism-cancer/

Metformin, Thyroid-Pituitary Axis, Diabetes Mellitus, and Metabolism

Larry H, Bernstein, MD, FCAP, Author and Curator
and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/9/27/2014/Metformin,_thyroid-pituitary_ axis,_diabetes_mellitus,_and_metabolism

Autophagy-Modulating Proteins and Small Molecules Candidate Targets for Cancer Therapy: Commentary of Bioinformatics Approaches

Author and Curator: Larry H Bernstein, MD, FCAP and Article Architect: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/09/18/autophagy-modulating-proteins-and-small-molecules-candidate-targets-for-cancer-therapy-commentary-of-bioinformatics-approaches/

 

Neural Activity Regulating Endocrine Response

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/02/13/neural-activity-regulating-endocrine-response/

 

Pituitary Neuroendocrine Axis

Writer and Curator: Larry H. Bernstein, MD, FCA

https://pharmaceuticalintelligence.com/2015/02/04/pituitary-neuroendocrine-axis/

On the Influence of Hormones on Cancer

VOLUME 4: Human Reproductive System, Genomic Endocrinology and Cancer Types

(Series D: BioMedicine & Immunology) Kindle Edition. On Amazon.com  since February 2, 2021

http://www.amazon.com/dp/B08VTFWVKM

Read Full Post »


Inhibitory CD161 receptor recognized as a potential immunotherapy target in glioma-infiltrating T cells by single-cell analysis

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

 

Brain tumors, especially the diffused Gliomas are of the most devastating forms of cancer and have so-far been resistant to immunotherapy. It is comprehended that T cells can penetrate the glioma cells, but it still remains unknown why infiltrating cells miscarry to mount a resistant reaction or stop the tumor development.

Gliomas are brain tumors that begin from neuroglial begetter cells. The conventional therapeutic methods including, surgery, chemotherapy, and radiotherapy, have accomplished restricted changes inside glioma patients. Immunotherapy, a compliance in cancer treatment, has introduced a promising strategy with the capacity to penetrate the blood-brain barrier. This has been recognized since the spearheading revelation of lymphatics within the central nervous system. Glioma is not generally carcinogenic. As observed in a number of cases, the tumor cells viably reproduce and assault the adjoining tissues, by and large, gliomas are malignant in nature and tend to metastasize. There are four grades in glioma, and each grade has distinctive cell features and different treatment strategies. Glioblastoma is a grade IV glioma, which is the crucial aggravated form. This infers that all glioblastomas are gliomas, however, not all gliomas are glioblastomas.

Decades of investigations on infiltrating gliomas still take off vital questions with respect to the etiology, cellular lineage, and function of various cell types inside glial malignancies. In spite of the available treatment options such as surgical resection, radiotherapy, and chemotherapy, the average survival rate for high-grade glioma patients remains 1–3 years (1).

A recent in vitro study performed by the researchers of Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard, USA, has recognized that CD161 is identified as a potential new target for immunotherapy of malignant brain tumors. The scientific team depicted their work in the Cell Journal, in a paper entitled, “Inhibitory CD161 receptor recognized in glioma-infiltrating T cells by single-cell analysis.” on 15th February 2021.

To further expand their research and findings, Dr. Kai Wucherpfennig, MD, PhD, Chief of the Center for Cancer Immunotherapy, at Dana-Farber stated that their research is additionally important in a number of other major human cancer types such as 

  • melanoma,
  • lung,
  • colon, and
  • liver cancer.

Dr. Wucherpfennig has praised the other authors of the report Mario Suva, MD, PhD, of Massachusetts Common Clinic; Aviv Regev, PhD, of the Klarman Cell Observatory at Broad Institute of MIT and Harvard, and David Reardon, MD, clinical executive of the Center for Neuro-Oncology at Dana-Farber.

Hence, this new study elaborates the effectiveness of the potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes.

The Study-

IMAGE SOURCE: Experimental Strategy (Mathewson et al., 2021)

 

The group utilized single-cell RNA sequencing (RNA-seq) to mull over gene expression and the clonal picture of tumor-infiltrating T cells. It involved the participation of 31 patients suffering from diffused gliomas and glioblastoma. Their work illustrated that the ligand molecule CLEC2D activates CD161, which is an immune cell surface receptor that restrains the development of cancer combating activity of immune T cells and tumor cells in the brain. The study reveals that the activation of CD161 weakens the T cell response against tumor cells.

Based on the study, the facts suggest that the analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 that codes for CD161 as a candidate inhibitory receptor. This was followed by the use of 

  • CRISPR/Cas9 gene-editing technology to inactivate the KLRB1 gene in T cells and showed that CD161 inhibits the tumor cell-killing function of T cells. Accordingly,
  • genetic inactivation of KLRB1 or
  • antibody-mediated CD161 blockade

enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other forms of human cancers. The work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immune checkpoint targets.

Further, it has been identified that many cancer patients are being treated with immunotherapy drugs that disable their “immune checkpoints” and their molecular brakes are exploited by the cancer cells to suppress the body’s defensive response induced by T cells against tumors. Disabling these checkpoints lead the immune system to attack the cancer cells. One of the most frequently targeted checkpoints is PD-1. However, recent trials of drugs that target PD-1 in glioblastomas have failed to benefit the patients.

In the current study, the researchers found that fewer T cells from gliomas contained PD-1 than CD161. As a result, they said, “CD161 may represent an attractive target, as it is a cell surface molecule expressed by both CD8 and CD4 T cell subsets [the two types of T cells engaged in response against tumor cells] and a larger fraction of T cells express CD161 than the PD-1 protein.”

However, potential side effects of antibody-mediated blockade of the CLEC2D-CD161 pathway remain unknown and will need to be examined in a non-human primate model. The group hopes to use this finding in their future work by

utilizing their outline by expression of KLRB1 gene in tumor-infiltrating T cells in diffuse gliomas to make a remarkable contribution in therapeutics related to immunosuppression in brain tumors along with four other common human cancers ( Viz. melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma, and colorectal cancer) and how this may be manipulated for prevalent survival of the patients.

References

(1) Anders I. Persson, QiWen Fan, Joanna J. Phillips, William A. Weiss, 39 – Glioma, Editor(s): Sid Gilman, Neurobiology of Disease, Academic Press, 2007, Pages 433-444, ISBN 9780120885923, https://doi.org/10.1016/B978-012088592-3/50041-4.

Main Source

Mathewson ND, Ashenberg O, Tirosh I, Gritsch S, Perez EM, Marx S, et al. 2021. Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis. Cell.https://www.cell.com/cell/fulltext/S0092-8674(21)00065-9?elqTrackId=c3dd8ff1d51f4aea87edd0153b4f2dc7

Related Articles

VIDEOS on Cancer Biology, Cancer Genetics, Cancer Immunotherapy

19th Annual Koch Institute Summer Symposium on Cancer Immunotherapy, June 12, 2020 at MIT’s Kresge Auditorium

 

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

 

Single Cell Sequencing:

Part 4.1 in Genomics Volume 2

Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology 

On Amazon.com since 12/28/2019

https://www.amazon.com/dp/B08385KF87

 

4.1.3   Single-cell Genomics: Directions in Computational and Systems Biology – Contributions of Prof. Aviv Regev @Broad Institute of MIT and Harvard, Cochair, the Human Cell Atlas Organizing Committee with Sarah Teichmann of the Wellcome Trust Sanger Institute

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/09/03/single-cell-genomics-directions-in-computational-and-systems-biology-contributions-of-ms-aviv-regev-phd-broad-institute-of-mit-and-harvard-cochair-the-human-cell-atlas-organizing-committee-wit/

 

4.1.4   Cellular Genetics

https://www.sanger.ac.uk/science/programmes/cellular-genetics

 

4.1.5   Cellular Genomics

https://www.garvan.org.au/research/cellular-genomics

 

4.1.6   SINGLE CELL GENOMICS 2019 – sometimes the sum of the parts is greater than the whole, September 24-26, 2019, Djurönäset, Stockholm, Sweden http://www.weizmann.ac.il/conferences/SCG2019/single-cell-genomics-2019

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2019/05/29/single-cell-genomics-2019-september-24-26-2019-djuronaset-stockholm-sweden/

 

4.1.7   Norwich Single-Cell Symposium 2019, Earlham Institute, single-cell genomics technologies and their application in microbial, plant, animal and human health and disease, October 16-17, 2019, 10AM-5PM

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2019/06/04/norwich-single-cell-symposium-2019-earlham-institute-single-cell-genomics-technologies-and-their-application-in-microbial-plant-animal-and-human-health-and-disease-october-16-17-2019-10am-5pm/

 

4.1.8   Newly Found Functions of B Cell

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

https://pharmaceuticalintelligence.com/2019/05/23/newly-found-functions-of-b-cell/

 

4.1.9 RESEARCH HIGHLIGHTS: HUMAN CELL ATLAS

https://www.broadinstitute.org/research-highlights-human-cell-atlas

 

CRISPR – 200 articles in the Journal

 

Chapter 21 in Genomics Volume 1

Genomics Orientations for Personalized Medicine. On Amazon.com since 11/23/2015

http://www.amazon.com/dp/B018DHBUO6

 

Glioblastoma – 150 articles in the Journal

Most recent

 

Immunotherapy may help in glioblastoma survival

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

https://pharmaceuticalintelligence.com/2019/03/16/immunotherapy-may-help-in-glioblastoma-survival/

 

New Treatment in Development for Glioblastoma: Hopes for Sen. John McCain

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/07/25/new-treatment-in-development-for-glioblastoma-hopes-for-sen-john-mccain/

 

Funding Oncorus’s Immunotherapy Platform: Next-generation Oncolytic Herpes Simplex Virus (oHSV) for Brain Cancer, Glioblastoma Multiforme (GBM)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/28/funding-oncoruss-immunotherapy-platform-next-generation-oncolytic-herpes-simplex-virus-ohsv-for-brain-cancer-glioblastoma-multiforme-gbm/

 

Glioma, Glioblastoma and Neurooncology

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/10/19/glioma-glioblastoma-and-neurooncology/

 

Positron Emission Tomography (PET) and Near-Infrared Fluorescence Imaging:  Noninvasive Imaging of Cancer Stem Cells (CSCs)  monitoring of AC133+ glioblastoma in subcutaneous and intracerebral xenograft tumors

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/29/positron-emission-tomography-pet-and-near-infrared-fluorescence-imaging-noninvasive-imaging-of-cancer-stem-cells-cscs-monitoring-of-ac133-glioblastoma-in-subcutaneous-and-intracerebral-xenogra/

 

Gamma Linolenic Acid (GLA) as a Therapeutic tool in the Management of Glioblastoma

Eric Fine* (1), Mike Briggs* (1,2), Raphael Nir# (1,2,3)

https://pharmaceuticalintelligence.com/2013/07/15/gamma-linolenic-acid-gla-as-a-therapeutic-tool-in-the-management-of-glioblastoma/

 

 

Read Full Post »


Noninvasive blood test can detect cancer 4 years before conventional diagnosis

Reporter : Irina Robu, PhD

Several international researchers at  Fudan University and at Singlera Genomics have developed a noninvasive blood test, PanSeer that can detect whether a patient with five common type of cancers such as stomach, esophageal, colorectal, lung and liver cancer; four years before the condition can be diagnosed by the current methods. Early detection is significant for the reason that the survival of cancer patients increases when the disease is identified at early stages, as the tumor can be surgically removed or treated with suitable drugs. Yet, only a partial number of early screening tests exist for a few cancer types.

The blood test detected cancer in 91 percent of samples from individuals who have been asymptomatic when the samples were collected, but only diagnosed with cancer one to four years later. It was found that the test can accurately detect cancer in 88 percent from samples of 113 patience who were diagnosed. The blood test also detects cancer free samples 95 percent of the time.

What is clear is that the study is unique, in that the scientists had access to blood samples from patients who were asymptomatic but not diagnosed yet. This permitted the researchers to design a test that can find a cancer marker much earlier than conventional diagnosis. The sample were collected as part of 10-year longitudinal study started in 2007 by Fudan University in China.

The researchers highlight that the PanSeer assay is improbable to predict which patients will later go on to develop cancer. As a substitute, it is most possible identifying patients who already have cancerous growths, but continue  to be asymptomatic for current detection methods. The team decided that further large-scale longitudinal studies are needed to confirm the potential of the test for the early detection of cancer in pre-diagnosis individuals.

SOURCE

https://www.universityofcalifornia.edu/news/non-invasive-blood-test-can-detect-cancer-4-years-conventional-diagnosis-methods?utm_source=fiat-lux

Read Full Post »


National Cancer Institute Director Neil Sharpless says mortality from delays in cancer screenings due to COVID19 pandemic could result in tens of thousands of extra deaths in next decade

Reporter: Stephen J Williams, PhD

Source: https://cancerletter.com/articles/20200619_1/

NCI Director’s Report

Sharpless: COVID-19 expected to increase mortality by at least 10,000 deaths from breast and colorectal cancers over 10 years

By Matthew Bin Han Ong

This story is part of The Cancer Letter’s ongoing coverage of COVID-19’s impact on oncology. A full list of our coverage, as well as the latest meeting cancellations, is available here.

The COVID-19 pandemic will likely cause at least 10,000 excess deaths from breast cancer and colorectal cancer over the next 10 years in the United States.

Scenarios run by NCI and affiliated modeling groups predict that delays in screening for and diagnosis of breast and colorectal cancers will lead to a 1% increase in deaths through 2030. This translates into 10,000 additional deaths, on top of the expected one million deaths resulting from these two cancers.

“For both these cancer types, we believe the pandemic will influence cancer deaths for at least a decade,” NCI Director Ned Sharpless said in a virtual joint meeting of the Board of Scientific Advisors and the National Cancer Advisory Board June 15. “I find this worrisome as cancer mortality is common. Even a 1% increase every decade is a lot of cancer suffering.

“And this analysis, frankly, is pretty conservative. We do not consider cancers other than those of breast and colon, but there is every reason to believe the pandemic will affect other types of cancer, too. We did not account for the additional non-lethal morbidity from upstaging, but this could also be significant and burdensome.”

An editorial by Sharpless on this subject appears in the journal Science.

The early analyses, conducted by the institute’s Cancer Intervention and Surveillance Modeling Network, focused on breast and colorectal cancers, because these are common, with relatively high screening rates.

CISNET modelers created four scenarios to assess long-term increases in cancer mortality rates for these two diseases:

  1. The pandemic has no effect on cancer mortality

 

  1. Delayed screening—with 75% reduction in mammography and, colorectal screening and adenoma surveillance for six months

 

  1. Delayed diagnosis—with one-third of people delaying follow-up after a positive screening or diagnostic mammogram, positive FIT or clinical symptoms for six months during a six-month period

 

  1. Combination of scenarios two and three

 

Treatment scenarios after diagnosis were not included in the model. These would be: delays in treatment, cancellation of treatment, or modified treatment.

“What we did is show the impact of the number of excess deaths per year for 10 years for each year starting in 2020 for scenario four versus scenario one,” Eric “Rocky” Feuer, chief of the NCI’s Statistical Research and Applications Branch in the Surveillance Research Program, said to The Cancer Letter.

Feuer is the overall project scientist for CISNET, a collaborative group of investigators who use simulation modeling to guide public health research and priorities.

“The results for breast cancer were somewhat larger than for colorectal,” Feuer said. “And that’s because breast cancer has a longer preclinical natural history relative to colorectal cancer.”

Modelers in oncology are creating a global modeling consortium, COVID-19 and Cancer Taskforce, to “support decision-making in cancer control both during and after the crisis.” The consortium is supported by the Union for International Cancer Control, The International Agency for Research on Cancer, The International Cancer Screening Network, the Canadian Partnership Against Cancer, and Cancer Council NSW, Australia.

A spike in cancer mortality rates threatens to reverse or slow down—at least in the medium term—the steady trend of reduction of cancer deaths. On Jan. 8, the American Cancer Society published its annual estimates of new cancer cases and deaths, declaring that the latest data—from 2016 to 2017—show the “largest ever single-year drop in overall cancer mortality of 2.2%.” Experts say that innovation in lung cancer treatment and the success of smoking cessation programs are driving the sharp decrease (The Cancer LetterFeb. 7, 2020).

The pandemic is expected to have broader impact, including increases in mortality rates for other cancer types. Also, variations in severity of COVID-19 in different regions in the U.S. will influence mortality metrics.

“There’s some other cancers that might have delays in screening—for example cervical, prostate, and lung cancer, although lung cancer screening rates are still quite low and prostate cancer screening should only be conducted on those who determine that the benefits outweigh the harms,” Feuer said. “So, those are the major screening cancers, but impacts of delays in treatment, canceling treatment or alternative treatments—could impact a larger range of cancer sites.

“This model assumes a moderate disruption which resolves after six months, and doesn’t consider non-lethal morbidities associated with the delay. One thing I think probably is occurring is regional variation in these impacts,” Feuer said. “If you’re living in New York City where things were ground zero for some of the worst impact early on, probably delays were larger than other areas of the country. But now, as we’re seeing upticks in other areas of the country, there may be in impact in these areas as well”

How can health care providers mitigate some of these harms? For example, for people who delayed screening and diagnosis, are providers able to perform triage, so that those at highest risk are prioritized?

“From a strictly cancer control point of view, let’s get those people who delayed screening, or followup to a positive test, or treatment back on schedule as soon as possible,” Feuer said. “But it’s not a simple calculus, because in every situation, we have to weigh the harms and benefits. As we come out of the pandemic, it tips more and more to, ‘Let’s get back to business with respect to cancer control.’

“Telemedicine doesn’t completely substitute for seeing patients in person, but at least people could get the advice they need, and then are triaged through their health care providers to indicate if they really should prioritize coming in. That helps the individual and the health care provider  weigh the harms and benefits, and try to strategize about what’s best for any individual.”

If the pandemic continues to disrupt routine care, cancer-related mortality rates would rise beyond the predictions in this model.

“I think this analysis begins to help us understand the costs with regard to cancer outcomes of the pandemic,” Sharpless said. “Let’s all agree we will do everything in our power to minimize these adverse effects, to protect our patients from cancer suffering.”

 

For more Articles on COVID-19 please see our Coronavirus Portal at

https://pharmaceuticalintelligence.com/coronavirus-portal/

 

Read Full Post »


Live Conference Coverage AACR 2020 in Real Time: Monday June 22, 2020 8AM-Noon Sessions

Reporter: Stephen J. Williams, PhD

Follow Live in Real Time using

#AACR20

@pharma_BI

@AACR

 

Register for FREE at https://www.aacr.org/

AACR VIRTUAL ANNUAL MEETING II

 

June 22-24: Free Registration for AACR Members, the Cancer Community, and the Public
This virtual meeting will feature more than 120 sessions and 4,000 e-posters, including sessions on cancer health disparities and the impact of COVID-19 on clinical trials

 

This Virtual Meeting is Part II of the AACR Annual Meeting.  Part I was held online in April and was centered only on clinical findings.  This Part II of the virtual meeting will contain all the Sessions and Abstracts pertaining to basic and translational cancer research as well as clinical trial findings.

 

REGISTER NOW

 

Monday, June 22

8:30 AM – 10:10 AM EDT

Virtual Special Session

Opening Ceremony

The Opening Ceremony will include the following presentations:
Welcome from AACR CEO Margaret Foti, PhD, MD (hc)

CHIEF EXECUTIVE OFFICER

MARGARET FOTI, PHD, MD (HC)

​American Association for Cancer Research
Philadelphia, Pennsylvania

  • Dr. Foti mentions that AACR is making progress in including more ethnic and gender equality in cancer research and she feels that the disparities seen in health care, and in cancer care, is related to the disparities seen in the cancer research profession
  • AACR is very focused now on blood cancers and creating innovation summits on this matter
  • In 2019 awarded over 60 grants but feel they will be able to fund more research in 2020
  • Government funding is insufficient at current levels

Remarks from AACR Immediate Past President Elaine R. Mardis, PhD, FAACR

  • involved in planning and success of the first virtual meeting (it was really well done)
  • # of registrants was at unprecedented numbers
  • the scope for this meeting will be wider than the first meeting
  • they have included special sessions including COVID19 and health disparities
  • 70 educational and methodology workshops on over 70 channels

AACR Award for Lifetime Achievement in Cancer Research

  • Dr. Philip Sharp is awardee of Lifetime Achievement Award
  • Dr. Sharp is known for his work in RNA splicing and development of multiple cancer models including a mouse CRSPR model
  • worked under Jim Watson at Cold Spring Harbor
    Presentation of New Fellows of the AACR Academy
  • Dr. Radcliffe for hypoxic factors
  • CART therapies
  • Dr. Semenza for HIF1 discovery
  • Dr Swanton for stratification of patients and tumor heterogeneity
  • these are just some of the new fellows

AACR-Biedler Prizes for Cancer Journalism

  • Writer of Article War of Nerves awarded; reported on nerve intervation of tumors
  • writer Budman on reporting and curation of hedgehog inhibitors in cancers
  • patient advocacy book was awarded for journalism
  • cancer survivor Kasie Newsome produced multiple segments on personalized cancer therapy from a cancer survivor perspective

Remarks from Speaker of the United States House of Representatives Nancy Pelosi

  • helped secure a doubling of funding for NCI and NIH in the 90s
  • securing COVID funding to offset some of the productivity issues related to the shutdown due to COVID
  • advocating for more work to alleviate health disparities

 

Remarks from United States Senator Roy Blunt

  • tireless champion in the Senate for cancer research funding; he was a cancer survivor himself
  • we need to keep focus on advances in science

Margaret Foti

DETAILS

Monday, June 22

10:10 AM – 12:30 PM EDT

Virtual Plenary Session

Bioinformatics and Systems Biology, Epidemiology, Immunology, Molecular and Cellular Biology/Genetics

Opening Plenary Session: Turning Science into Lifesaving Care

Alexander Marson, Antoni Ribas, Ashani T Weeraratna, Olivier Elemento, Howard Y Chang, Daniel D. De Carvalho

DETAILS

Monday, June 22

12:45 PM – 1:30 PM EDT

Awards and Lectures

How should we think about exceptional and super responders to cancer therapy? What biologic insights might ensue from considering these cases? What are ways in which considering super responders may lead to misleading conclusions? What are the pros and cons of the quest to locate exceptional and super responders?

Alice P Chen, Vinay K Prasad, Celeste Leigh Pearce

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Tumor Biology, Immunology

Experimental and Molecular Therapeutics, Immunology

Other Articles on this Open Access  Online Journal on Cancer Conferences and Conference Coverage in Real Time Include

Press Coverage

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Symposium: New Drugs on the Horizon Part 3 12:30-1:25 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on NCI Activities: COVID-19 and Cancer Research 5:20 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Novel Targets and Therapies 2:35 PM

 

Read Full Post »


Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Reporter: Stephen J. Williams, PhD

 Minisymposium: Evaluating Cancer Genomics from Normal Tissues through Evolution to Metastatic Disease

Oncologic therapy shapes the fitness landscape of clonal hematopoiesis

April 28, 2020, 4:10 PM – 4:20 PM

Presenter/Authors
Kelly L. Bolton, Ryan N. Ptashkin, Teng Gao, Lior Braunstein, Sean M. Devlin, Minal Patel, Antonin Berthon, Aijazuddin Syed, Mariko Yabe, Catherine Coombs, Nicole M. Caltabellotta, Mike Walsh, Ken Offit, Zsofia Stadler, Choonsik Lee, Paul Pharoah, Konrad H. Stopsack, Barbara Spitzer, Simon Mantha, James Fagin, Laura Boucai, Christopher J. Gibson, Benjamin Ebert, Andrew L. Young, Todd Druley, Koichi Takahashi, Nancy Gillis, Markus Ball, Eric Padron, David Hyman, Jose Baselga, Larry Norton, Stuart Gardos, Virginia Klimek, Howard Scher, Dean Bajorin, Eder Paraiso, Ryma Benayed, Maria Arcilla, Marc Ladanyi, David Solit, Michael Berger, Martin Tallman, Montserrat Garcia-Closas, Nilanjan Chatterjee, Luis Diaz, Ross Levine, Lindsay Morton, Ahmet Zehir, Elli Papaemmanuil. Memorial Sloan Kettering Cancer Center, New York, NY, University of North Carolina at Chapel Hill, Chapel Hill, NC, University of Cambridge, Cambridge, United Kingdom, Dana-Farber Cancer Institute, Boston, MA, Washington University, St Louis, MO, The University of Texas MD Anderson Cancer Center, Houston, TX, Moffitt Cancer Center, Tampa, FL, National Cancer Institute, Bethesda, MD

Abstract
Recent studies among healthy individuals show evidence of somatic mutations in leukemia-associated genes, referred to as clonal hematopoiesis (CH). To determine the relationship between CH and oncologic therapy we collected sequential blood samples from 525 cancer patients (median sampling interval time = 23 months, range: 6-53 months) of whom 61% received cytotoxic therapy or external beam radiation therapy and 39% received either targeted/immunotherapy or were untreated. Samples were sequenced using deep targeted capture-based platforms. To determine whether CH mutational features were associated with tMN risk, we performed Cox proportional hazards regression on 9,549 cancer patients exposed to oncologic therapy of whom 75 cases developed tMN (median time to transformation=26 months). To further compare the genetic and clonal relationships between tMN and the proceeding CH, we analyzed 35 cases for which paired samples were available. We compared the growth rate of the variant allele fraction (VAF) of CH clones across treatment modalities and in untreated patients. A significant increase in the growth rate of CH mutations was seen in DDR genes among those receiving cytotoxic (p=0.03) or radiation therapy (p=0.02) during the follow-up period compared to patients who did not receive therapy. Similar growth rates among treated and untreated patients were seen for non-DDR CH genes such as DNMT3A. Increasing cumulative exposure to cytotoxic therapy (p=0.01) and external beam radiation therapy (2×10-8) resulted in higher growth rates for DDR CH mutations. Among 34 subjects with at least two CH mutations in which one mutation was in a DDR gene and one in a non-DDR gene, we studied competing clonal dynamics for multiple gene mutations within the same patient. The risk of tMN was positively associated with CH in a known myeloid neoplasm driver mutation (HR=6.9, p<10-6), and increased with the total number of mutations and clone size. The strongest associations were observed for mutations in TP53 and for CH with mutations in spliceosome genes (SRSF2, U2AF1 and SF3B1). Lower hemoglobin, lower platelet counts, lower neutrophil counts, higher red cell distribution width and higher mean corpuscular volume were all positively associated with increased tMN risk. Among 35 cases for which paired samples were available, in 19 patients (59%), we found evidence of at least one of these mutations at the time of pre-tMN sequencing and in 13 (41%), we identified two or more in the pre-tMN sample. In all cases the dominant clone at tMN transformation was defined by a mutation seen at CH Our serial sampling data provide clear evidence that oncologic therapy strongly selects for clones with mutations in the DDR genes and that these clones have limited competitive fitness, in the absence of cytotoxic or radiation therapy. We further validate the relevance of CH as a predictor and precursor of tMN in cancer patients. We show that CH mutations detected prior to tMN diagnosis were consistently part of the dominant clone at tMN diagnosis and demonstrate that oncologic therapy directly promotes clones with mutations in genes associated with chemo-resistant disease such as TP53.

  • therapy resulted also in clonal evolution and saw changes in splice variants and spliceosome
  • therapy promotes current DDR mutations
  • clonal hematopoeisis due to selective pressures
  • mutations, variants number all predictive of myeloid disease
  • deferring adjuvant therapy for breast cancer patients with patients in highest MDS risk group based on biomarkers, greatly reduced their risk for MDS

5704 – Pan-cancer genomic characterization of patient-matched primary, extracranial, and brain metastases

Presenter/AuthorsOlivia W. Lee, Akash Mitra, Won-Chul Lee, Kazutaka Fukumura, Hannah Beird, Miles Andrews, Grant Fischer, John N. Weinstein, Michael A. Davies, Jason Huse, P. Andrew Futreal. The University of Texas MD Anderson Cancer Center, TX, The University of Texas MD Anderson Cancer Center, TX, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, AustraliaDisclosures O.W. Lee: None. A. Mitra: None. W. Lee: None. K. Fukumura: None. H. Beird: None. M. Andrews: ; Merck Sharp and Dohme. G. Fischer: None. J.N. Weinstein: None. M.A. Davies: ; Bristol-Myers Squibb. ; Novartis. ; Array BioPharma. ; Roche and Genentech. ; GlaxoSmithKline. ; Sanofi-Aventis. ; AstraZeneca. ; Myriad Genetics. ; Oncothyreon. J. Huse: None. P. Futreal: None.

Abstract: Brain metastases (BM) occur in 10-30% of patients with cancer. Approximately 200,000 new cases of brain metastases are diagnosed in the United States annually, with median survival after diagnosis ranging from 3 to 27 months. Recently, studies have identified significant genetic differences between BM and their corresponding primary tumors. It has been shown that BM harbor clinically actionable mutations that are distinct from those in the primary tumor samples. Additional genomic profiling of BM will provide deeper understanding of the pathogenesis of BM and suggest new therapeutic approaches.
We performed whole-exome sequencing of BM and matched tumors from 41 patients collected from renal cell carcinoma (RCC), breast cancer, lung cancer, and melanoma, which are known to be more likely to develop BM. We profiled total 126 fresh-frozen tumor samples and performed subsequent analyses of BM in comparison to paired primary tumor and extracranial metastases (ECM). We found that lung cancer shared the largest number of mutations between BM and matched tumors (83%), followed by melanoma (74%), RCC (51%), and Breast (26%), indicating that cancer type with high tumor mutational burden share more mutations with BM. Mutational signatures displayed limited differences, suggesting a lack of mutagenic processes specific to BM. However, point-mutation heterogeneity revealed that BM evolve separately into different subclones from their paired tumors regardless of cancer type, and some cancer driver genes were found in BM-specific subclones. These models and findings suggest that these driver genes may drive prometastatic subclones that lead to BM. 32 curated cancer gene mutations were detected and 71% of them were shared between BM and primary tumors or ECM. 29% of mutations were specific to BM, implying that BM often accumulate additional cancer gene mutations that are not present in primary tumors or ECM. Co-mutation analysis revealed a high frequency of TP53 nonsense mutation in BM, mostly in the DNA binding domain, suggesting TP53 nonsense mutation as a possible prerequisite for the development of BM. Copy number alteration analysis showed statistically significant differences between BM and their paired tumor samples in each cancer type (Wilcoxon test, p < 0.0385 for all). Both copy number gains and losses were consistently higher in BM for breast cancer (Wilcoxon test, p =1.307e-5) and lung cancer (Wilcoxon test, p =1.942e-5), implying greater genomic instability during the evolution of BM.
Our findings highlight that there are more unique mutations in BM, with significantly higher copy number alterations and tumor mutational burden. These genomic analyses could provide an opportunity for more reliable diagnostic decision-making, and these findings will be further tested with additional transcriptomic and epigenetic profiling for better characterization of BM-specific tumor microenvironments.

  • are there genomic signatures different in brain mets versus non metastatic or normal?
  • 32 genes from curated databases were different between brain mets and primary tumor
  • frequent nonsense mutations in TP53
  • divergent clonal evolution of drivers in BMets from primary
  • they were able to match BM with other mutational signatures like smokers and lung cancer signatures

5707 – A standard operating procedure for the interpretation of oncogenicity/pathogenicity of somatic mutations

Presenter/AuthorsPeter Horak, Malachi Griffith, Arpad Danos, Beth A. Pitel, Subha Madhavan, Xuelu Liu, Jennifer Lee, Gordana Raca, Shirley Li, Alex H. Wagner, Shashikant Kulkarni, Obi L. Griffith, Debyani Chakravarty, Dmitriy Sonkin. National Center for Tumor Diseases, Heidelberg, Germany, Washington University School of Medicine, St. Louis, MO, Mayo Clinic, Rochester, MN, Georgetown University Medical Center, Washington, DC, Dana-Farber Cancer Institute, Boston, MA, Frederick National Laboratory for Cancer Research, Rockville, MD, University of Southern California, Los Angeles, CA, Sunquest, Boston, MA, Baylor College of Medicine, Houston, TX, Memorial Sloan Kettering Cancer Center, New York, NY, National Cancer Institute, Rockville, MDDisclosures P. Horak: None. M. Griffith: None. A. Danos: None. B.A. Pitel: None. S. Madhavan: ; Perthera Inc. X. Liu: None. J. Lee: None. G. Raca: None. S. Li: ; Sunquest Information Systems, Inc. A.H. Wagner: None. S. Kulkarni: ; Baylor Genetics. O.L. Griffith: None. D. Chakravarty: None. D. Sonkin: None.AbstractSomatic variants in cancer-relevant genes are interpreted from multiple partially overlapping perspectives. When considered in discovery and translational research endeavors, it is important to determine if a particular variant observed in a gene of interest is oncogenic/pathogenic or not, as such knowledge provides the foundation on which targeted cancer treatment research is based. In contrast, clinical applications are dominated by diagnostic, prognostic, or therapeutic interpretations which in part also depends on underlying variant oncogenicity/pathogenicity. The Association for Molecular Pathology, the American Society of Clinical Oncology, and the College of American Pathologists (AMP/ASCO/CAP) have published structured somatic variant clinical interpretation guidelines which specifically address diagnostic, prognostic, and therapeutic implications. These guidelines have been well-received by the oncology community. Many variant knowledgebases, clinical laboratories/centers have adopted or are in the process of adopting these guidelines. The AMP/ASCO/CAP guidelines also describe different data types which are used to determine oncogenicity/pathogenicity of a variant, such as: population frequency, functional data, computational predictions, segregation, and somatic frequency. A second collaborative effort created the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets to provide a harmonized vocabulary that provides an evidence-based ranking system of molecular targets that supports their value as clinical targets. However, neither of these clinical guideline systems provide systematic and comprehensive procedures for aggregating population frequency, functional data, computational predictions, segregation, and somatic frequency to consistently interpret variant oncogenicity/pathogenicity, as has been published in the ACMG/AMP guidelines for interpretation of pathogenicity of germline variants. In order to address this unmet need for somatic variant oncogenicity/pathogenicity interpretation procedures, the Variant Interpretation for Cancer Consortium (VICC, a GA4GH driver project) Knowledge Curation and Interpretation Standards (KCIS) working group (WG) has developed a Standard Operating Procedure (SOP) with contributions from members of ClinGen Somatic Clinical Domain WG, and ClinGen Somatic/Germline variant curation WG using an approach similar to the ACMG/AMP germline pathogenicity guidelines to categorize evidence of oncogenicity/pathogenicity as very strong, strong, moderate or supporting. This SOP enables consistent and comprehensive assessment of oncogenicity/pathogenicity of somatic variants and latest version of an SOP can be found at https://cancervariants.org/wg/kcis/.

  • best to use this SOP for somatic mutations and not rearangements
  • variants based on oncogenicity as strong to weak
  • useful variant knowledge on pathogenicity curated from known databases
  • the recommendations would provide some guideline on curating unknown somatic variants versus known variants of hereditary diseases
  • they have not curated RB1 mutations or variants (or for other RBs like RB2? p130?)

 

Follow on Twitter at:

@pharma_BI

@AACR

@CureCancerNow

@pharmanews

@BiotechWorld

#AACR20

 

Read Full Post »


Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on Signaling in Cancer 11:45am-1:30 pm

Reporter: Stephen J. Williams, PhD.

SESSION VMS.MCB01.01 – Emerging Signaling Vulnerabilities in Cancer
April 27, 2020, 11:45 AM – 1:30 PM
Virtual Meeting: All Session Times Are U.S. EDT
DESCRIPTION

All session times are U.S. Eastern Daylight Time (EDT). Access to AACR Virtual Annual Meeting I sessions are free with registration. Register now at http://www.aacr.org/virtualam2020

Session Type

Virtual Minisymposium

Track(s)

Molecular and Cellular Biology/Genetics

16 Presentations
11:45 AM – 1:30 PM
– Chairperson

J. Silvio Gutkind. UCSD Moores Cancer Center, La Jolla, CA

11:45 AM – 1:30 PM
– Chairperson

  • in 80’s and 90’s signaling focused on defects and also oncogene addiction.  Now the field is switching to finding vulnerabilities in signaling cascades in cancer

Adrienne D. Cox. University of North Carolina at Chapel Hill, Chapel Hill, NC

11:45 AM – 11:55 AM
– Introduction

J. Silvio Gutkind. UCSD Moores Cancer Center, La Jolla, CA

11:55 AM – 12:05 PM
1085 – Interrogating the RAS interactome identifies EFR3A as a novel enhancer of RAS oncogenesis

Hema Adhikari, Walaa Kattan, John F. Hancock, Christopher M. Counter. Duke University, Durham, NC, University of Texas MD Anderson Cancer Center, Houston, TX

Abstract: Activating mutations in one of the three RAS genes (HRAS, NRAS, and KRAS) are detected in as much as a third of all human cancers. As oncogenic RAS mediates it tumorigenic signaling through protein-protein interactions primarily at the plasma membrane, we sought to document the protein networks engaged by each RAS isoform to identify new vulnerabilities for future therapeutic development. To this end, we determined interactomes of oncogenic HRAS, NRAS, and KRAS by BirA-mediated proximity labeling. This analysis identified roughly ** proteins shared among multiple interactomes, as well as a smaller subset unique to a single RAS oncoprotein. To identify those interactome components promoting RAS oncogenesis, we created and screened sgRNA library targeting the interactomes for genes modifying oncogenic HRAS-, NRAS-, or KRAS-mediated transformation. This analysis identified the protein EFR3A as not only a common component of all three RAS interactomes, but when inactivated, uniformly reduced the growth of cells transformed by any of the three RAS isoforms. EFR3A recruits a complex containing the druggable phosphatidylinositol (Ptdlns) 4 kinase alpha (PI4KA) to the plasma membrane to generate the Ptdlns species PI4P. We show that EFR3A sgRNA reduced multiple RAS effector signaling pathways, suggesting that EFR3A acts at the level of the oncoprotein itself. As lipids play a critical role in the membrane localization of RAS, we tested and found that EFR3A sgRNA reduced not only the occupancy of RAS at the plasma membrane, but also the nanoclustering necessary for signaling. Furthermore, the loss of oncogenic RAS signaling induced by EFR3A sgRNA was rescued by targeting PI4K to the plasma membrane. Taken together, these data support a model whereby EFR3A recruits PI4K to oncogenic RAS to promote plasma membrane localization and nonclustering, and in turn, signaling and transformation. To investigate the therapeutic potential of this new RAS enhancer, we show that EFR3A sgRNA reduced oncogenic KRAS signaling and transformed growth in a panel of pancreatic ductal adenocarcinoma (PDAC) cell lines. Encouraged by these results we are exploring whether genetically inactivating the kinase activity of PI4KA inhibits oncogenic signaling and transformation in PDAC cell lines. If true, pharmacologically targeting PI4K may hold promise as a way to enhance the anti-neoplastic activity of drugs targeting oncogenic RAS or its effectors.

@DukeU

@DukeMedSchool

@MDAndersonNews

  • different isoforms of ras mutations exist differentially in various tumor types e.g. nras vs kras
  • the C terminal end serve as hotspots of mutations and probably isoform specific functions
  • they determined the interactomes of nras and kras and determined how many candidates are ras specific
  • they overlayed results from proteomic and CRSPR screen; EFR3a was a potential target that stuck out
  • using TCGA patients with higher EFR3a had poorer prognosis
  • EFR3a promotes Ras signaling; and required for RAS driven tumor growth (in RAS addicted tumors?)
  • EGFR3a promotes clustering of oncogenic RAS at plasma membrane

 

12:05 PM – 12:10 PM
– Discussion

12:10 PM – 12:20 PM
1086 – Downstream kinase signaling is dictated by specific KRAS mutations; Konstantin Budagyan, Jonathan Chernoff. Drexel University College of Medicine, Philadelphia, PA, Fox Chase Cancer Center, Philadelphia, PA @FoxChaseCancer

Abstract: Oncogenic KRAS mutations are common in colorectal cancer (CRC), found in ~50% of tumors, and are associated with poor prognosis and resistance to therapy. There is substantial diversity of KRAS alleles observed in CRC. Importantly, emerging clinical and experimental analysis of relatively common KRAS mutations at amino acids G12, G13, A146, and Q61 suggest that each mutation differently influences the clinical properties of a disease and response to therapy. For example, KRAS G12 mutations confer resistance to EGFR-targeted therapy, while G13D mutations do not. Although there is clinical evidence to suggest biological differences between mutant KRAS alleles, it is not yet known what drives these differences and whether they can be exploited for allele-specific therapy. We hypothesized that different KRAS mutants elicit variable alterations in downstream signaling pathways. To investigate this hypothesis, we created a novel system by which we can model KRAS mutants in isogenic mouse colon epithelial cell lines. To generate the cell lines, we developed an assay using fluorescent co-selection for CRISPR-driven genome editing. This assay involves simultaneous introduction of single-guide RNAs (sgRNAs) to two different endogenous loci resulting in double-editing events. We first introduced Cas9 and blue fluorescent protein (BFP) into mouse colon epithelial cell line containing heterozygous KRAS G12D mutation. We then used sgRNAs targeting BFP and the mutant G12D KRAS allele along with homology-directed repair (HDR) templates for a GFP gene and a KRAS mutant allele of our choice. Cells that successfully undergo HDR are GFP-positive and contain the desired KRAS mutation. Therefore, selection for GFP-positive cells allows us to identify those with phenotypically silent KRAS edits. Ultimately, this method allows us to toggle between different mutant alleles while preserving the wild-type allele, all in an isogenic background. Using this method, we have generated cell lines with endogenous heterozygous KRAS mutations commonly seen in CRC (G12D, G12V, G12C, G12R, G13D). In order to elucidate cellular signaling pathway differences between the KRAS mutants, we screened the mutated cell lines using a small-molecule library of ~160 protein kinase inhibitors. We found that there are mutation-specific differences in drug sensitivity profiles. These observations suggest that KRAS mutants drive specific cellular signaling pathways, and that further exploration of these pathways may prove to be valuable for identification of novel therapeutic opportunities in CRC.

  • Flourescent coselection of KRAS edits by CRSPR screen in a colorectal cancer line; a cell that is competent to undergo HR can undergo combination multiple KRAS
  • target only mutant allele while leaving wild type intact;
  • it was KRAS editing event in APC  +/- mouse cell line
  • this enabled a screen for kinase inhibitors that decreased tumor growth in isogenic cell lines; PKC alpha and beta 1 inhibitors, also CDK4 inhibitors inhibited cell growth
  • questions about heterogeneity in KRAS clones; they looked at off target guides and looked at effects in screens; then they used top two clones that did not have off target;  questions about 3D culture- they have not done that; Question ? dependency on AKT activity? perhaps the G12E has different downstream effectors

 

12:20 PM – 12:25 PM
– Discussion

12:25 PM – 12:35 PM
1087 – NF1 regulates the RAS-related GTPases, RRAS and RRAS2, independent of RAS activity; Jillian M. Silva, Lizzeth Canche, Frank McCormick. University of California, San Francisco, San Francisco, CA @UCSFMedicine

Abstract: Neurofibromin, which is encoded by the neurofibromatosis type 1 (NF1) gene, is a tumor suppressor that acts as a RAS-GTPase activating protein (RAS-GAP) to stimulate the intrinsic GTPase activity of RAS as well as the closely related RAS subfamily members, RRAS, RRAS2, and MRAS. This results in the conversion of the active GTP-bound form of RAS into the inactive GDP-bound state leading to the downregulation of several RAS downstream effector pathways, most notably MAPK signaling. While the region of NF1 that regulates RAS activity represents only a small fraction of the entire protein, a large extent of the NF1 structural domains and their corresponding mechanistic functions remain uncharacterized despite the fact there is a high frequency of NF1 mutations in several different types of cancer. Thus, we wanted to elucidate the underlying biochemical and signaling functions of NF1 that are unrelated to the regulation of RAS and how loss of these functions contributes to the pathogenesis of cancer. To accomplish this objective, we used CRISPR-Cas9 methods to knockout NF1 in an isogenic “RASless” MEF model system, which is devoid of the major oncogenic RAS isoforms (HRAS, KRAS, and NRAS) and reconstituted with the KRAS4b wild-type or mutant KRASG12C or KRASG12D isoform. Loss of NF1 led to elevated RAS-GTP levels, however, this increase was not as profound as the levels in KRAS-mutated cells or provided a proliferative advantage. Although ablation of NF1 resulted in sustained activation of MAPK signaling, it also unexpectedly, resulted in a robust increase in AKT phosphorylation compared to KRAS-mutated cells. Surprisingly, loss of NF1 in KRAS4b wild-type and KRAS-mutated cells potently suppressed the RAS-related GTPases, RRAS and RRAS2, with modest effects on MRAS, at both the transcript and protein levels. A Clariom™D transcriptome microarray analysis revealed a significant downregulation in the NF-κB target genes, insulin-like growth factor binding protein 2 (IGFBP2), argininosuccinate synthetase 1 (ASS1), and DUSP1, in both the NF1 knockout KRAS4b wild-type and KRAS-mutated cells. Moreover, NF1Null melanoma cells also displayed a potent suppression of RRAS and RRAS2 as well as these NF-κB transcription factors. Since RRAS and RRAS2 both contain the same NF-κB transcription factor binding sites, we hypothesize that IGFBP2, ASS1, and/or DUSP1 may contribute to the NF1-mediated regulation of these RAS-related GTPases. More importantly, this study provides the first evidence of at least one novel RAS-independent function of NF1 to regulate the RAS-related subfamily members, RRAS and RRAS2, in a manner exclusive of its RAS-GTPase activity and this may provide insight into new potential biomarkers and molecular targets for treating patients with mutations in NF1.
  • NF1 and SPRED work together to signal from RTK cKIT through RAS
  • NF1 knockout cells had higher KRAS and had increased cell proliferation
  • NF1 -/-  or SPRED loss had increased ERK phosphorylation and some increase in AKT activity compared to parental cells
  • they used isogenic cell lines devoid of all RAS isoforms and then reconstituted with specific RAS WT or mutants
  • NF1 and SPRED KO both reduce RRAS expression; in an AKT independent mannner
  • NF1 SPRED KO cells have almost no IGFBP2 protein expression and SNAIL so maybe affecting EMT?
  • this effect is independent of its RAS GTPAse activity (noncanonical)

12:35 PM – 12:40 PM
– Discussion

12:40 PM – 12:50 PM
1088 – Elucidating the regulation of delayed-early gene targets of sustained MAPK signaling; Kali J. Dale, Martin McMahon. University of Utah, Salt Lake City, UT, Huntsman Cancer Institute, Salt Lake City, UT

Abstract: RAS and its downstream effector, BRAF, are commonly mutated proto-oncogenes in many types of human cancer. Mutationally activated RAS or BRAF signal through the MEK→ERK MAP kinase (MAPK) pathway to regulate key cancer cell hallmarks such as cell division cycle progression, reduced programmed cell death, and enhanced cell motility. Amongst the list of RAS/RAF-regulated genes are those encoding integrins, alpha-beta heterodimeric transmembrane proteins that regulate cell adhesion to the extracellular matrix. Altered integrin expression has been linked to the acquisition of more aggressive behavior by melanoma, lung, and breast cancer cells leading to diminished survival of cancer patients. We have previously documented the ability of the RAS-activated MAPK pathway to induce the expression of ITGB3 encoding integrin β3 in several different cell types. RAS/RAF-mediated induction of ITGB3 mRNA requires sustained, high-level activation of RAF→MEK→ERK signaling mediated by oncogene activation and is classified as “delayed-early”, in that it is sensitive to the protein synthesis inhibitor cycloheximide. However, to date, the regulatory mechanisms that allow for induced ITGB3 downstream of sustained, high-level activation of MAPK signaling remains obscure. We have identified over 300 DEGs, including those expressing additional cell surface proteins, that display similar regulatory characteristics as ITGB3. We use integrin β3 as a model to test our hypothesis that there is a different mechanism of regulation for delayed-early genes (DEG) compared to the canonical regulation of Immediate-Early genes. There are three regions in the chromatin upstream of the ITGB3 that become more accessible during RAF activation. We are relating the chromatin changes seen during RAF activation to active enhancer histone marks. To elucidate the essential genes of this regulation process, we are employing the use of a genome-wide CRISPR knockout screen. The work presented from this abstract will help elucidate the regulatory properties of oncogenic progression in BRAF mutated cancers that could lead to the identification of biomarkers.

12:50 PM – 12:55 PM
– Discussion

12:55 PM – 1:05 PM
1090 – Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis

Radha Mukherjee, Kiran Gireesan Vanaja, Jacob A. Boyer, Juan Qiu, Xiaoping Chen, Elisa De Stanchina, Sarat Chandarlapaty, Andre Levchenko, Neal Rosen. Memorial Sloan Kettering Cancer Center, New York, NY, Yale University, West Haven, CT, Memorial Sloan Kettering Cancer Center, New York, NY, Memorial Sloan Kettering Cancer Center, New York, NY @sloan_kettering

Abstract: The PI3K pathway is a key regulator of metabolism, cell proliferation and migration and some of its components (e.g. PIK3CA and PTEN) are frequently altered in cancer by genetic events that deregulate its output. However, PI3K signaling is not usually the primary driver of these tumors and inhibitors of components of the pathway have only modest antitumor effects. We now show that both physiologic and oncogenic activation of the PI3K signaling by growth factors and an activating hotspot PIK3CA mutation respectively, cause an increase in the expression of the lipid phosphatase PTEN, thus limiting the duration of the signal and the output of the pathway in tumors. Pharmacologic and physiologic inhibition of the pathway by HER2/PI3K/AKT/mTOR inhibitors and nutrient starvation respectively reduce PTEN, thus buffering the effects of inhibition and contributing to the rebound in pathway activity that occurs in tumors. This regulation is found to be a feature of multiple types of cancer, non-cancer cell line and PDX models thereby highlighting its role as a key conserved feedback loop within the PI3K signaling network, both in vitro and in vivo. Regulation of expression is due to mTOR/4EBP1 dependent control of PTEN translation and is lost when 4EBP1 is knocked out. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in reducing the output of oncogenic mutants that deregulate the pathway and the antitumor activity of PI3K pathway inhibitors.

  • mTOR can be a potent regulator of PTEN and therefore a major issue when developing PI3K inhibitors

1:05 PM – 1:10 PM
– Discussion

1:10 PM – 1:20 PM
1091 – BI-3406 and BI 1701963: Potent and selective SOS1::KRAS inhibitors induce regressions in combination with MEK inhibitors or irinotecan

Daniel Gerlach, Michael Gmachl, Juergen Ramharter, Jessica Teh, Szu-Chin Fu, Francesca Trapani, Dirk Kessler, Klaus Rumpel, Dana-Adriana Botesteanu, Peter Ettmayer, Heribert Arnhof, Thomas Gerstberger, Christiane Kofink, Tobias Wunberg, Christopher P. Vellano, Timothy P. Heffernan, Joseph R. Marszalek, Mark Pearson, Darryl B. McConnell, Norbert Kraut, Marco H. Hofmann. Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria, The University of Texas MD Anderson Cancer Center, Houston, TX, The University of Texas MD Anderson Cancer Center, Houston, TX, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

  • there is rational for developing an SOS1 inhibitor (GEF); BI3406 shows better PK and PD as a candidate
  • most sensitive cell lines to inhibitor carry KRAS mutation; NRAS or BRAF mutations are not sensititve
  • KRAS mutation defines sensitivity so they created KRAS mut isogenic cell lines
  • found best to co inhibit SOS and MEK as observed plasticity with only SOS
  • dual combination in lung NSCLC pancreatic showed enhanced efficacy compared to monotherapy
  • SOS1 inhibition plus irinotecan enhances DNA double strand breaks; no increased DNA damage in normal stroma but preferentially in tumor cells
  • these SOS1 had broad activity against KRAS mutant models;
  • phase 1 started in 2019;

@Boehringer

1:20 PM – 1:25 PM
– Discussion

1:25 PM – 1:30 PM
– Closing Remarks

Adrienne D. Cox. University of North Carolina at Chapel Hill, Chapel Hill, NC

Follow on Twitter at:

@pharma_BI

@AACR

@GenomeInstitute

@CureCancerNow

@UCLAJCCC

#AACR20

#AACR2020

#curecancernow

#pharmanews

Read Full Post »


Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Opening Remarks and Clinical Session 9 am

Reporter: Stephen J. Williams, PhD.

9:00 AM Opening Session

9:00 AM – 9:05 AM
– Opening Video

9:05 AM – 9:15 AM
– AACR President: Opening Remarks Elaine R. Mardis. Nationwide Children’s Hospital, Columbus, OH

 

Dr. Mardis is the Robert E. and Louise F. Dunn Distinguished Professor of Medicine @GenomeInstitute at Washington University of St. Louis School of Medicine.

Opening remarks:  Dr. Mardis gave her welcome from her office.  She expressed many thanks to healthcare workers and the hard work of scientists and researchers.  She also expressed some regret for the many scientists who had wonderful research to present and how hard it was to make the decision to go virtual however she feels there now more than ever still needs a venue to discuss scientific and clinical findings.  Some of the initiatives that she has had the opportunity to engage in the areas of groundbreaking discoveries and clinical trials.  606,000 lives will be lost in US this year from cancer.  AACR is being vigilant as also an advocacy platform and public policy platform in Congress and Washington.  The AACR has been at the front of public policy on electronic cigarettes.  Blood Cancer Discovery is their newest journal.  They are going to host joint conferences with engineers, mathematicians and physicists to discuss how they can help to transform oncology.  Cancer Health Disparity Annual Conference is one of the fastest growing conferences.  They will release a report later this year about the scope of the problem and policy steps needed to alleviate these disparities.  Lack of racial and ethnic minorities in cancer research had been identified an issue and the AACR is actively working to reduce the disparities within the ranks of cancer researchers.   Special thanks to Dr. Margaret Foti for making the AACR the amazing organization it is.

 

9:15 AM – 9:30 AM- AACR Annual Meeting Program Chair: Review of Program for AACR Virtual Annual Meeting Antoni Ribas. UCLA Medical Center, Los Angeles, CA

Antoni Ribas, MD PhD is Professor, Medicine, Surgery, Molecular and Medical Pharmacology; Director, Parker Institute for Cancer Immunotherapy Center at UCLA; Director, UCLA Jonsson Comprehensive Cancer Center Tumor Immunology Program aribas@mednet.ucla.edu

The AACR felt it was important to keep the discourse in the cancer research field as the Annual AACR meeting is the major way scientists and clinicians discuss the latest and most pertinent results.  A three day virtual meeting June 22-24 will focus more on the translational and basic research while this meeting is more focused on clinical trials.  There will be educational programs during the June virtual meeting.  The COVID in Cancer part of this virtual meeting was put in specially for this meeting and there will be a special meeting on this in July.  They have created an AACR COVID task force.  The AACR has just asked Congress and NIH to extend the grants due to the COVID induced shutdown of many labs.

9:30  Open Clinical Plenary Session (there are 17 sessions today but will only cover a few of these)

9:30 AM – 9:31 AM
– Chairperson Nilofer S. Azad. Johns Hopkins Sidney Kimmel Comp. Cancer Center, Baltimore, MD @noza512

9:30 AM – 9:31 AM
– Chairperson Manuel Hidalgo. Weill Cornell Medicine, New York, NY

9:30 AM – 9:35 AM
– Introduction Nilofer S. Azad. Johns Hopkins Sidney Kimmel Comp. Cancer Center, Baltimore, MD

9:35 AM – 9:45 AM
CT011 – Evaluation of durvalumab in combination with olaparib and paclitaxel in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL Lajos Pusztai, et al

see https://www.abstractsonline.com/pp8/#!/9045/presentation/10593

AbstractBackground: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint risk to evaluate novel agents as neoadjuvant therapy for breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/is ypN0)). DNA repair deficiency in cancer cells can lead to immunogenic neoantigens, activation of the STING pathway, and PARP inhibition can also upregulate PD-L1 expression. Based on these rationales we tested the combination of durvalumab (anti-PDL1), olaparib (PARP inhibitor) and paclitaxel in I-SPY2.
Methods: Women with tumors ≥ 2.5 cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone receptor positive (HR+) patients had to have MammaPrint high molecular profile. Treatment included durvalumab 1500 mg every 4 weeks x 3, olaparib 100 mg twice daily through weeks 1-11 concurrent with paclitaxel 80 mg/m2 weekly x 12 (DOP) followed by doxorubicin/cyclophosphamide (AC) x 4. The control arm was weekly paclitaxel x 12 followed by AC x 4. All patients undergo serial MRI imaging and imaging response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Regimens “graduation with success” when the Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial in the appropriate biomarker groups reaches > 85%.
Results: A total of 73 patients received DOP treatment including 21 HR- tumors (i.e. triple-negative breast cancer, TNBC) and 52 HR+ tumors between May 2018 – June 2019. The control group included 299 patients with HER2- tumors. The DOP arm graduated in June 2019, 13 months after enrollment had started, for all HER2- negative and the HR+/HER2- cohorts with > 0.85% predictive probabilities of success. 72 patient completed surgery and evaluable for pCR, the final predicted probabilities of success in a future phase III trial to demonstrate higher pCR rate with DOP compared to control are 81% for all HER2- cancers (estimated pCR rate 37%), 80% for TNBC (estimated pCR rate 47%) and 74.5% for HR+/HER2- patients (estimated pCR rate 28%). Association between pCR and germline BRCA status and immune gene expression including PDL1 will be presented at the meeting. No unexpected toxicities were seen, but 10 patients (14%) had possibly immune or olaparib related grade 2/3 AEs (3 pneumonitis, 2 adrenal insufficiency, 1 colitis, 1 pancreatitis, 2 elevated LFT, 1 skin toxicity, 2 hypothyroidism, 1 hyperthyroidism, 1 esophagitis).
Conclusion: I-SPY2 demonstrated a significant improvement in pCR with durvalumab and olaparib included with paclitaxel compared to chemotherapy alone in women with stage II/III high-risk, HER2-negative breast cancer, improvement was seen in both the HR+ and TNBC subsets.

  • This combination of durvalumab and olaparib is safe in triple negative breast cancer
  • expected synergy between PARP inhibitors and PDL1 inhibitors as olaparib inhibits DNA repair and would increase the mutational burden, which is in lung cancer shown to be a biomarker for efficacy of immune checkpoint inhibitors such as Opdivio
  • three subsets of breast cancers were studied: her2 negative, triple negative and ER+ tumors
  • MRI imaging tumor size was used as response
  • olaparib arm had elevation of liver enzymes and there was a pancreatitis
  • however paclitaxel was used within the combination as well as a chemo arm but the immuno arm alone may not be better than chemo alone but experimental arm with all combo definitely better than chemo alone
  • they did not look at BRCA1/2 status, followup talk showed that this is a select group that may see enhanced benefit; PARP inhibitors were seen to be effective only in BRCA1/2 mutant ovarian cancer previously

 

10:10 AM – 10:20 AM
CT012 – Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial Grant A. McArthur,

for abstract please see https://www.abstractsonline.com/pp8/#!/9045/presentation/10594

AbstractBackground: Approved systemic treatments for advanced melanoma include immune checkpoint inhibitor therapy (CIT) and targeted therapy with BRAF plus MEK inhibitors for BRAFV600E/K mutant melanoma. Response rates with CITs are typically lower than those observed with targeted therapy, but CIT responses are more durable. Preclinical and clinical data suggest a potential for synergy between CIT and BRAF plus MEK inhibitors. We therefore evaluated whether combining CIT with targeted therapy could improve efficacy vs targeted therapy alone. Methods: Treatment-naive patients with unresectable stage IIIc/IV melanoma (AJCC 7th ed), measurable disease by RECIST 1.1, and BRAFV600 mutations in their tumors were randomized to the anti­-programmed death-ligand 1 antibody A + C + V or placebo (Pbo) + C + V. A or Pbo were given on days 1 and 15 of each 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. The primary outcome was investigator-assessed progression-free survival (PFS). Results: 514 patients were enrolled (A + C + V = 256; Pbo + C + V = 258) and followed for a median of 18.9 months. Investigator-assessed PFS was significantly prolonged with A + C + V vs Pbo + C + V (15.1 vs 10.6 months, respectively; hazard ratio: 0.78; 95% confidence interval: 0.63-0.97; P=0.025), an effect seen in all prognostic subgroups. While objective response rates were similar in the A + C + V and Pbo + C + V groups, median duration of response was prolonged with A + C + V (21.0 months) vs Pbo + C + V (12.6 months). Overall survival data were not mature at the time of analysis. Common treatment-related adverse events (AEs; >30%) in the A + C + V and Pbo + C + V groups were blood creatinine phosphokinase (CPK) increase (51.3% vs 44.8%), diarrhea (42.2% vs 46.6%), rash (40.9% in both arms), arthralgia (39.1% vs 28.1%), pyrexia (38.7% vs 26.0%), alanine aminotransferase (ALT) increase (33.9% vs 22.8%), and lipase increase (32.2% vs 27.4%). Common treatment-related grade 3/4 AEs (>10%) that occurred in the A + C + V and Pbo + C + V groups were lipase increase (20.4% vs 20.6%), blood CPK increase (20.0% vs 14.9%), ALT increase (13.0% vs 8.9%), and maculopapular rash (12.6% vs 9.6%). The incidence of treatment-related serious AEs was similar between the A + C + V (33.5%) and Pbo + C + V (28.8%) groups. 12.6% of patients in the A + C + V group and 15.7% in the Pbo + C + V group stopped all treatment because of AEs. The safety profile of the A + C + V regimen was generally consistent with the known profiles of the individual components. Conclusion: Combination therapy with A + C + V was tolerable and manageable, produced durable responses, and significantly increased PFS vs Pbo + C + V. Thus, A + C + V represents a viable treatment option for BRAFV600 mutation-positive advanced melanoma. ClinicalTrials.gov ID: NCT02908672

 

 

10:25 AM – 10:35 AM
CT013 – SWOG S1320: Improved progression-free survival with continuous compared to intermittent dosing with dabrafenib and trametinib in patients with BRAF mutated melanoma Alain Algazi,

for abstract and more author information please see https://www.abstractsonline.com/pp8/#!/9045/presentation/10595

AbstractBackground: BRAF and MEK inhibitors yield objective responses in the majority of BRAFV600E/K mutant melanoma patients, but acquired resistance limits response durations. Preclinical data suggests that intermittent dosing of these agents may delay acquired resistance by deselecting tumor cells that grow optimally in the presence of these agents. S1320 is a randomized phase 2 clinical trial designed to determine whether intermittent versus continuous dosing of dabrafenib and trametinib improves progression-free survival (PFS) in patients with advanced BRAFV600E/K melanoma.
Methods: All patients received continuous dabrafenib and trametinib for 8-weeks after which non-progressing patients were randomized to receive either continuous treatment or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. Unscheduled treatment interruptions of both drugs for > 14 days were not permitted. Responses were assessed using RECIST v1.1 at 8-week intervals scheduled to coincide with on-treatment periods for patients on the intermittent dosing arm. Adverse events were assessed using CTCAE v4 monthly. The design assumed exponential PFS with a median of 9.4 months using continuous dosing, 206 eligible patients and 156 PFS events. It had 90% power with a two-sided α = 0.2 to detect a change to a median with an a priori hypothesis that intermittent dosing would improve the median PFS to 14.1 months using a Cox model stratified by the randomization stratification factors.
Results: 242 patients were treated and 206 patients without disease progression after 8 weeks were randomized, 105 to continuous and 101 to intermittent treatment. 70% of patients had not previously received immune checkpoint inhibitors. There were no significant differences between groups in terms of baseline patient characteristics. The median PFS was statistically significantly longer, 9.0 months from randomization, with continuous dosing vs. 5.5 months from randomization with intermittent dosing (p = 0.064). There was no difference in overall survival between groups (median OS = 29.2 months in both arms p = 0.93) at a median follow up of 2 years. 77% of patient treated continuously discontinued treatment due to disease progression vs. 84% treated intermittently (p = 0.34).
Conclusions: Continuous dosing with the BRAF and MEK inhibitors dabrafenib and trametinib yields superior PFS compared with intermittent dosing.

  • combo of MEK and BRAF inhibitors can attract immune cells like TREGs so PDL1 inhibitor might help improve outcome
  • PFS was outcome endpoint
  • LDH was elevated in three patients (why are they seeing liver tox?  curious like previous study); are seeing these tox with the PDL1 inhibitors
  • there was marked survival over placebo group and PFS was statistically  with continuous dosing however intermittent dosing shows no improvement

Dr. Wafik el Diery gave a nice insight as follows

Follow on Twitter at:

@pharma_BI

@AACR

@GenomeInstitute

@CureCancerNow

@UCLAJCCC

#AACR20

#AACR2020

#curecancernow

#pharmanews

 

 

 

Read Full Post »


Opinion Articles from the Lancet: COVID-19 and Cancer Care in China and Africa

Reporter: Stephen J. Williams, PhD

Cancer Patients in SARS-CoV-2 infection: a nationwide analysis in China

Wenhua Liang, Weijie Guan, Ruchong Chen, Wei Wang, Jianfu Li, Ke Xu, Caichen Li, Qing Ai, Weixiang Lu, Hengrui Liang, Shiyue Li, Jianxing He

Lancet Oncol. 2020 Mar; 21(3): 335–337. Published online 2020 Feb 14. doi: 10.1016/S1470-2045(20)30096-6

PMCID: PMC7159000

 

The National Clinical Research Center for Respiratory Disease and the National Health Commission of the People’s Republic of China collaborated to establish a prospective cohort to monitor COVID-19 cases in China.  As on Jan31, 20202007 cases have been collected and analyzed with confirmed COVID-19 infection in these cohorts.

Results: 18 or 1% of COVID-19 cases had a history of cancer (the overall average cancer incidence in the overall China population is 0.29%) {2015 statistics}.  It appeared that cancer patients had an observable higher risk of COVID related complications upon hospitalization. However, this was a higher risk compared with the general population.  There was no comparison between cancer patients not diagnosed with COVID-19 and an assessment of their risk of infection.  Interestingly those who were also cancer survivors showed an increased incidence of COVID related severe complications compared to the no cancer group.

Although this study could have compared the risk within a cancer group, the authors still felt the results warranted precautions when dealing with cancer patients and issued recommendations including:

  1. Postponing of adjuvant chemotherapy or elective surgery for stable cancer should be considered
  2. Stronger personal protection for cancer patients
  3. More intensive surveillance or treatment should be considered when patients with cancer are infected, especially in older patients

Further studies will need to address the risk added by specific types of chemotherapy: cytolytic versus immunotherapy e.g.

 

Preparedness for COVID-19 in the oncology community in Africa

Lancet Oncology, Verna Vanderpuye, Moawia Mohammed,Ali Elhassan

Hannah Simonds: Published:April 03, 2020DOI:https://doi.org/10.1016/S1470-2045(20)30220-5

Africa has a heterogeneity of cultures, economies and disease patterns however fortunately it is one of the last countries to be hit by the COVID-19 pandemic, which allows some time for preparation by the African nations.  The authors note that with Africa’s previous experiences with epidemics, namely ebola and cholera, Africa should be prepared for this pandemic.

However, as a result of poor economic discipline, weak health systems, and poor health-seeking behaviors across the continent, outcomes could be dismal. Poverty, low health literacy rates, and cultural practices that negatively affect cancer outcomes will result in poor assimilation of COVID-19 containment strategies in Africa.”

In general African oncologists are following COVID-19 guidelines from other high-income countries, but as this writer acknowledges in previous posts, there was a significant lag from first cases in the United States to the concrete formulation of guidelines for both oncologists and patients with regard to this pandemic.  African oncologist are delaying the start of adjuvant therapies and switching more to oral therapies and rethink palliative care.

However the authors still have many more questions than answers, however even among countries that have dealt with this pandemic before Africa (like Italy and US), oncologists across the globe still have not been able to answer questions like: what if my patient develops a fever, what do I do during a period of neutropenia, to their satisfaction or the satisfaction of the patient.  These are questions even oncologists who are dealing in COVID hotspots are still trying to answer including what constitutes a necessary surgical procedure? As I have highlighted in recent posts, oncologists in New York have all but shut down all surgical procedures and relying on liquid biopsies taken in the at-home setting. But does Africa have this capability of access to at home liquid biopsy procedures?

In addition, as I had just highlighted in a recent posting, there exists extreme cancer health disparities across the African continent, as well as the COVID responses. In West Africa, COVID-19 protocols are defined at individual institutions.  This is more like the American system where even NCI designated centers were left to fashion some of their own guidelines initially, although individual oncologists had banded together to do impromptu meetings to discuss best practices. However this is fine for big institutions, but as in the US, there is a large rural population on the African continent with geographical barriers to these big centers. Elective procedures have been cancelled and small number of patients are seen by day.  This remote strategy actually may be well suited for African versus more developed nations, as highlighted in a post I did about mobile health app use in oncology, as this telemedicine strategy is rather new among US oncologists (reference my posts with the Town Hall meetings).

The situation is more complicated in South Africa where they are dealing with an HIV epidemic, where about 8 million are infected with HIV. Oncology services here are still expecting to run at full capacity as the local hospitals deal with the first signs of the COVID outbreak. In Sudan, despite low COVID numbers, cancer centers have developed contingency plans. and are deferring new referrals except for emergency cases.  Training sessions for staff have been developed.

For more articles in this online open access journal on Cancer and COVID-19 please see our

Coronovirus Portal
Responses to the #COVID-19 outbreak from Oncologists, Cancer Societies and the NCI: Important information for cancer patients

 

Read Full Post »


Personalized Medicine, Omics, and Health Disparities in Cancer:  Can Personalized Medicine Help Reduce the Disparity Problem?

Curator: Stephen J. Williams, PhD

In a Science Perspectives article by Timothy Rebbeck, health disparities, specifically cancer disparities existing in the sub-Saharan African (SSA) nations, highlighting the cancer incidence disparities which exist compared with cancer incidence in high income areas of the world [1].  The sub-Saharan African nations display a much higher incidence of prostate, breast, and cervix cancer and these cancers are predicted to double within the next twenty years, according to IARC[2].  Most importantly,

 the histopathologic and demographic features of these tumors differ from those in high-income countries

meaning that the differences seen in incidence may reflect a true health disparity as increases rates in these cancers are not seen in high income countries (HIC).

Most frequent male cancers in SSA include prostate, lung, liver, leukemia, non-Hodgkin’s lymphoma, and Kaposi’s sarcoma (a cancer frequently seen in HIV infected patients [3]).  In SSA women, breast and cervical cancer are the most common and these display higher rates than seen in high income countries.  In fact, liver cancer is seen in SSA females at twice the rate, and in SSA males almost three times the rate as in high income countries.

 

 

 

 

 

 

Reasons for cancer disparity in SSA

Patients with cancer are often diagnosed at a late stage in SSA countries.  This contrasts with patients from high income countries, which have their cancers usually diagnosed at an earlier stage, and with many cancers, like breast[4], ovarian[5, 6], and colon, detecting the tumor in the early stages is critical for a favorable outcome and prognosis[7-10].  In addition, late diagnosis also limits many therapeutic options for the cancer patient and diseases at later stages are much harder to manage, especially with respect to unresponsiveness and/or resistance of many therapies.  In addition, treatments have to be performed in low-resource settings in SSA, and availability of clinical lab work and imaging technologies may be limited.

Molecular differences in SSA versus HIC cancers which may account for disparities

Emerging evidence suggests that there are distinct molecular signatures with SSA tumors with respect to histotype and pathology.  For example Dr. Rebbeck mentions that Nigerian breast cancers were defined by increased mutational signatures associated with deficiency of the homologous recombination DNA repair pathway, pervasive mutations in the tumor suppressor gene TP53, mutations in GATA binding protein 3 (GATA3), and greater mutational burden, compared with breast tumors from African Americans or Caucasians[11].  However more research will be required to understand the etiology and causal factors related to this molecular distinction in mutational spectra.

It is believed that there is a higher rate of hereditary cancers in SSA. And many SSA cancers exhibit the more aggressive phenotype than in other parts of the world.  For example breast tumors in SSA black cases are twice as likely than SSA Caucasian cases to be of the triple negative phenotype, which is generally more aggressive and tougher to detect and treat, as triple negative cancers are HER2 negative and therefore are not a candidate for Herceptin.  Also BRCA1/2 mutations are more frequent in black SSA cases than in Caucasian SSA cases [12, 13].

Initiatives to Combat Health Disparities in SSA

Multiple initiatives are being proposed or in action to bring personalized medicine to the sub-Saharan African nations.  These include:

H3Africa empowers African researchers to be competitive in genomic sciences, establishes and nurtures effective collaborations among African researchers on the African continent, and generates unique data that could be used to improve both African and global health.

There is currently a global effort to apply genomic science and associated technologies to further the understanding of health and disease in diverse populations. These efforts work to identify individuals and populations who are at risk for developing specific diseases, and to better understand underlying genetic and environmental contributions to that risk. Given the large amount of genetic diversity on the African continent, there exists an enormous opportunity to utilize such approaches to benefit African populations and to inform global health.

The Human Heredity and Health in Africa (H3Africa) consortium facilitates fundamental research into diseases on the African continent while also developing infrastructure, resources, training, and ethical guidelines to support a sustainable African research enterprise – led by African scientists, for the African people. The initiative consists of 51 African projects that include population-based genomic studies of common, non-communicable disorders such as heart and renal disease, as well as communicable diseases such as tuberculosis. These studies are led by African scientists and use genetic, clinical, and epidemiologic methods to identify hereditary and environmental contributions to health and disease. To establish a foundation for African scientists to continue this essential work into the future work, the consortium also supports many crucial capacity building elements, such as: ethical, legal, and social implications research; training and capacity building for bioinformatics; capacity for biobanking; and coordination and networking.

The World Economic Forum’s Leapfrogging with Precision Medicine project 

This project is part of the World Economic Forum’s Shaping the Future of Health and Healthcare Platform

The Challenge

Advancing precision medicine in a way that is equitable and beneficial to society means ensuring that healthcare systems can adopt the most scientifically and technologically appropriate approaches to a more targeted and personalized way of diagnosing and treating disease. In certain instances, countries or institutions may be able to bypass, or “leapfrog”, legacy systems or approaches that prevail in developed country contexts.

The World Economic Forum’s Leapfrogging with Precision Medicine project will develop a set of tools and case studies demonstrating how a precision medicine approach in countries with greenfield policy spaces can potentially transform their healthcare delivery and outcomes. Policies and governance mechanisms that enable leapfrogging will be iterated and scaled up to other projects.

Successes in personalized genomic research in SSA

As Dr. Rebbeck states:

 Because of the underlying genetic and genomic relationships between Africans and members of the African diaspora (primarily in North America and Europe), knowledge gained from research in SSA can be used to address health disparities that are prevalent in members of the African diaspora.

For example members of the West African heritage and genomic ancestry has been reported to confer the highest genomic risk for prostate cancer in any worldwide population [14].

 

PERSPECTIVEGLOBAL HEALTH

Cancer in sub-Saharan Africa

  1. Timothy R. Rebbeck

See all authors and affiliations

Science  03 Jan 2020:
Vol. 367, Issue 6473, pp. 27-28
DOI: 10.1126/science.aay474

Summary/Abstract

Cancer is an increasing global public health burden. This is especially the case in sub-Saharan Africa (SSA); high rates of cancer—particularly of the prostate, breast, and cervix—characterize cancer in most countries in SSA. The number of these cancers in SSA is predicted to more than double in the next 20 years (1). Both the explanations for these increasing rates and the solutions to address this cancer epidemic require SSA-specific data and approaches. The histopathologic and demographic features of these tumors differ from those in high-income countries (HICs). Basic knowledge of the epidemiology, clinical features, and molecular characteristics of cancers in SSA is needed to build prevention and treatment tools that will address the future cancer burden. The distinct distribution and determinants of cancer in SSA provide an opportunity to generate knowledge about cancer risk factors, genomics, and opportunities for prevention and treatment globally, not only in Africa.

 

References

  1. Rebbeck TR: Cancer in sub-Saharan Africa. Science 2020, 367(6473):27-28.
  2. Parkin DM, Ferlay J, Jemal A, Borok M, Manraj S, N’Da G, Ogunbiyi F, Liu B, Bray F: Cancer in Sub-Saharan Africa: International Agency for Research on Cancer; 2018.
  3. Chinula L, Moses A, Gopal S: HIV-associated malignancies in sub-Saharan Africa: progress, challenges, and opportunities. Current opinion in HIV and AIDS 2017, 12(1):89-95.
  4. Colditz GA: Epidemiology of breast cancer. Findings from the nurses’ health study. Cancer 1993, 71(4 Suppl):1480-1489.
  5. Hamilton TC, Penault-Llorca F, Dauplat J: [Natural history of ovarian adenocarcinomas: from epidemiology to experimentation]. Contracept Fertil Sex 1998, 26(11):800-804.
  6. Garner EI: Advances in the early detection of ovarian carcinoma. J Reprod Med 2005, 50(6):447-453.
  7. Brockbank EC, Harry V, Kolomainen D, Mukhopadhyay D, Sohaib A, Bridges JE, Nobbenhuis MA, Shepherd JH, Ind TE, Barton DP: Laparoscopic staging for apparent early stage ovarian or fallopian tube cancer. First case series from a UK cancer centre and systematic literature review. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 2013, 39(8):912-917.
  8. Kolligs FT: Diagnostics and Epidemiology of Colorectal Cancer. Visceral medicine 2016, 32(3):158-164.
  9. Rocken C, Neumann U, Ebert MP: [New approaches to early detection, estimation of prognosis and therapy for malignant tumours of the gastrointestinal tract]. Zeitschrift fur Gastroenterologie 2008, 46(2):216-222.
  10. Srivastava S, Verma M, Henson DE: Biomarkers for early detection of colon cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2001, 7(5):1118-1126.
  11. Pitt JJ, Riester M, Zheng Y, Yoshimatsu TF, Sanni A, Oluwasola O, Veloso A, Labrot E, Wang S, Odetunde A et al: Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features. Nature communications 2018, 9(1):4181.
  12. Zheng Y, Walsh T, Gulsuner S, Casadei S, Lee MK, Ogundiran TO, Ademola A, Falusi AG, Adebamowo CA, Oluwasola AO et al: Inherited Breast Cancer in Nigerian Women. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2018, 36(28):2820-2825.
  13. Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH et al: Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Human mutation 2018, 39(5):593-620.
  14. Lachance J, Berens AJ, Hansen MEB, Teng AK, Tishkoff SA, Rebbeck TR: Genetic Hitchhiking and Population Bottlenecks Contribute to Prostate Cancer Disparities in Men of African Descent. Cancer research 2018, 78(9):2432-2443.

Other articles on Cancer Health Disparities and Genomics on this Online Open Access Journal Include:

Gender affects the prevalence of the cancer type
The Rutgers Global Health Institute, part of Rutgers Biomedical and Health Sciences, Rutgers University, New Brunswick, New Jersey – A New Venture Designed to Improve Health and Wellness Globally
Breast Cancer Disparities to be Sponsored by NIH: NIH Launches Largest-ever Study of Breast Cancer Genetics in Black Women
War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert
Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk
Ethics Behind Genetic Testing in Breast Cancer: A Webinar by Laura Carfang of survivingbreastcancer.org
Live Notes from @HarvardMed Bioethics: Authors Jerome Groopman, MD & Pamela Hartzband, MD, discuss Your Medical Mind
Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test
Study Finds that Both Women and their Primary Care Physicians Confusion over Ovarian Cancer Symptoms May Lead to Misdiagnosis

 

Read Full Post »

Older Posts »