Author Interviews, Biomarkers, Cancer Research, Genetic Research, Ovarian Cancer / 07.08.2023
Ovarian Cancer: Proteomics Study Allows Identification of Subtype Resistant to Chemotherapy
MedicalResearch.com Interview with:
Pei Wang, PhD
Professor, Department of Genetics and Genomic Sciences
Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Michael J. Birrer MD PhD
Director, Winthrop P. Rockefeller Cancer Institute
University of Arkansas for Medical Sciences
Little Rock, AR 72205
Amanda G. Paulovich MD PhD
Translational Science and Therapeutics Division
Fred Hutchinson Cancer Center
Seattle WA 98109
MedicalResearch.com: What is the background for this study? How common is serous ovarian cancer?
Response: Epithelial ovarian cancer accounts for >185,000 deaths/year worldwide. The most common subtype, high-grade serous ovarian cancer (HGSOC), accounts for 60% of deaths. Despite improvements in surgical and chemotherapeutic approaches, HGSOC mortality has not changed in decades. Five-year survival remains ~30% for the majority of patients.
Standard of care involves surgical debulking combined with adjuvant or neoadjuvant chemotherapy with carbo- or cisplatin in combination with a taxane. At diagnosis, HGSOC is among the most chemo-sensitive of all epithelial malignancies, with initial response rates of ~85%, presumably related to DNA repair defects. Platinum is thought primarily to drive the response rate, due to the lower single-agent response rate for taxanes.
Unfortunately, 10-20% of HGSOC patients have treatment-refractory disease at diagnosis, fail to respond to initial chemotherapy, and have a dismal prognosis. The poor response to subsequent therapy and median overall survival of ~12 months for these patients has not changed in 40 years.
Despite >30 years of literature studying platinum resistance in cancer, there currently is no way to distinguish refractory from sensitive HGSOCs prior to therapy. Consequently, patients with refractory disease experience the toxicity of platinum-based chemotherapy without benefit. Due to their rapid progression, they are commonly excluded from participating in clinical trials. Consequently, there is no ongoing clinical research that could identify effective therapeutic agents for these patients or provide insights into molecular mechanisms of refractory disease. “Right now, we can’t identify drug-resistant ovarian cancer patients up front,” said co-senior author Michael Birrer, MD, PhD, who directs UAMS’ Winthrop J. Rockefeller Cancer Institute. “We find them by default: They get sick and pass away so quickly that they can’t even be put on new clinical trials.”
To address this unmet clinical need, we performed proteogenomic analysis of treatment-naïve HGSOCs (chemo-sensitive and chemo-refractory) to identify molecular signatures of refractory HGSOC and to identify potential treatment targets.
Dr. Thomas[/caption]
Dr. Daniel Thomas MD PhD FRACP FRCPA
Program Leader, Blood Cancer
Precision Medicine Theme at the South Australia Health Medical Research Institute
Clinical Hematologist, Royal Adelaide Hospital
Associate Professor, Adelaide Medical School, The University of Adelaide
MedicalResearch.com: What is the background for this study? Would you briefly describe the condition of CMML?
Response: Chronic myelomonocytic leukemia (CMML) is a rare, but increasingly frequent, clonal stem cell disorder that results in hyperproliferation of inflammatory monocytes, a form of white blood cells. It features both myelodysplasia and myeloproliferation. CMML is most often found in older adults and leads to anemia, decreased quality of life, and an increased risk of acute myeloid leukemia (AML).
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that stimulates production, growth, differentiation, activation, and function of myeloid cells (monocytes, neutrophils, and eosinophils). In the presence of RAS-pathway mutations, a greater sensitivity to GM-CSF contributes to the hyperproliferation of myelocytes in myelodysplastic leukemias such as CMML, juvenile myelomonocytic leukemia (JMML), and acute myeloid leukemia (AML). In CMML, greater sensitivity to GM-CSF stimulates excessive monocytic precursor proliferation.
The PREACH-M Trial, which stands for PREcision Approach to CHronic Myelomonocytic Leukemia, assesses the efficacy of lenzilumab in addition to azacitidine in treatment-naïve CMML participants with RAS-pathway mutations (KRAS, NRAS, CBL) and separately high dose ascorbate in participants with TET2 mutations who do not have RAS-pathway mutations. The study is currently underway and actively enrolling. It is being conducted and funded by the South Australian Health and Medical Research Institute (SAHMRI). 
Dr. Kamath[/caption]
Dr. Suneel Kamath MD
Gastrointestinal Oncologist
Cleveland Clinic
Senior Author on this research
MedicalResearch.com: What is the background for this study?
Response: Colorectal cancer rates in young people under age 50 are skyrocketing and have been for the last 3-4 decades. We really don’t understand why because most cases (probably around 70%) are not genetic or hereditary, just random, unfortunate events. We suspect that it is some exposure(s) like excess consumption of red meat, processed foods, sugar-sweetened beverages, excess antibiotic use altering the microbiome, rising incidence of obesity or some other factors. We really don’t know why yet.
Our study used a technology called metabolomics, the study of breakdown products and production building blocks for our bodies, to look for differences in colorectal cancer in young people versus people that are older that developed colorectal cancer. Because metabolomics measures how each individual interacts with the exposures in our environment like diet, air quality, etc., it is a way to bridge the gap between our nature (determined by genetics) and nurture (determined by our exposures).
Dr. Lova Sun[/caption]
Lova L. Sun, MD, MSCE
Medical Oncology
Assistant Professor of Medicine
Hospital of the University of Pennsylvania
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: An common clinical question for patients with metastatic non-small cell lung cancer with long-term response to immunotherapy-based treatment is how long to continue treatment. The major clinical trials stopped immunotherapy at a maximum of 2 years, but in clinical practice many patients and clinicians continue treatment beyond this time point.
We conducted a retrospective study of lung cancer patients across the US with long-term response to immunotherapy, to compare survival between those who stopped treatment at 2 years vs those who continued beyond 2 years. We found that there was no statistically significant difference in survival between the two groups.
Dr. Ruiz[/caption]
John M. Ruiz, Ph.D
Associate Professor of Clinical Psychology
Department of Psychology
University of Arizona
Dr. Ruiz is the incoming editor-in-chief of the American Psychological Association (APA) journal, Health Psychology
Dr. Ruiz joined the U.S. Preventive Services Task Force in January 2022
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Skin cancer is the most common type of cancer in the United States, but it often does not cause serious complications or death. The Task Force’s recommendation on screening for skin cancer focuses on the effectiveness of visual skin exams for children and adults who do not have any symptoms. When reviewing the latest research, we found that there is currently not enough evidence to tell us whether or not screening people without signs or symptoms is beneficial. This is an I statement.
Dr. Fallah[/caption]
Mahdi Fallah, MD, PhD
Prof. Hamdy[/caption]
Freddie C. Hamdy FRCS, FMedSci
Nuffield Professor of Surgery, University of Oxford
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Prof. Donovan[/caption]
Jenny L. Donovan PhD, FMedSci
Professor of Social Medicine, University of Bristol
MedicalResearch.com: What is the background for this study?
Response: Prostate cancer is a common malignancy in men. Prostate cancer diagnosis is made largely through opportunistic screening with a PSA (Prostate Specific Antigen) blood test, followed by prostate biopsies. The ProtecT study, funded by the National Institute for Health and Care Research in the UK, is the largest randomised trial of treatment in screen-detected localised prostate cancer. The study began by testing 82,429 men between the ages of 50 and 69 years, across nine UK centres with a PSA blood test, followed by biopsies of the prostate if the PSA level was elevated. 2,664 men with clinically localised prostate cancer were found. From these, 1,643 (62%) agreed to be randomised to Surgery (radical prostatectomy to remove the prostate gland), Radiotherapy (external beam with a period of hormone treatment beforehand), or Active Monitoring (where men received regular checks and further investigations, with change to radical treatment as necessary). The men were carefully followed up for an average of 15 years. In parallel, the side-effects of treatments and quality of life of these men was investigated using patient-reported outcomes included in an annual study questionnaire completed for at least 12 years.
Dr. Levin[/caption]
Trevor Levin Ph.D.
Founder and CEO of Convergent Genomics that produces the Uroamp assay
San Francisco, CA
MedicalResearch.com: What is the background for this study?
Response: Bladder cancer is one of the most expensive and challenging to diagnose and treat. Therefore, identifying cost-effective urine bladder cancer biomarkers to complement or replace the gold-standard invasive and costly cystoscopy for the early detection and monitoring of this highly recurrent disease is crucial. At the international Agency for research on Cancer (IARC-WHO), we have developed a simple urine-based assay TERT promoter mutations, the most common mutations in bladder cancer, and showed that the urine biomarker could detect bladder cancer patients at diagnosis but many years prior to clinical diagnosis. However, in this study, we wanted to see whether a more comprehensive genomic profiling of urine samples collected years prior to clinical diagnosis of bladder cancer could identify even more patients before they develop any symptoms.
The study was based on the UroAmp test, a general urine test that identifies mutations in 60 genes, developed by the Oregon Health Science University spin out company, Convergent Genomics. Drawing on previous research to identify genetic mutations linked to bladder cancer, the research team narrowed the new test down to focus on mutations within just ten genes.
Working with colleagues from the Tehran University of Medical Sciences in Iran, they trialled the potential new test using samples from the Golestan Cohort Study, which has tracked the health of more than 50,000 participants over ten years, all of whom provided urine samples at recruitment. Forty people within the study developed bladder cancer during that decade, and the team were able to test urine samples from twenty-nine of them, along with samples from 98 other similar participants as controls.
Dr. Koh[/caption]
Andrew Y. Koh, M.D.
Associate Professor, Pediatrics and Microbiology
Dr. Mosley[/caption]
Jonathan Mosley, MD, PhD
Associate Professor
Division of Clinical Pharmacology
Departments of Internal Medicine and Biomedical Informatics
Vanderbilt University Medical Center
MedicalResearch.com: What is the background for this study?
Response: Prostate cancer is an important source of morbidity and mortality among men. Earlier detection of disease is essential to reduce these adverse outcomes. Prostate cancer is heritable, and many single nucleotide polymorphisms (SNPs) associated with disease risk have been identified. Thus, there is considerable interest in using tools such as polygenic risk scores, which measure the burden of genetic risk variants an individual carries, to identify men at elevated risk of disease.
Dr. Tsirigos[/caption]
Aristotelis Tsirigos, Ph.D.
Professor of Medicine and Pathology
Co-director, Precision Medicine
Director, Applied Bioinformatics Laboratories
Dr. Sally Lau[/caption]
Dr. Sally Lau MD
Medical oncologist, NYU Langone’s Perlmutter Cancer Center
Assistant professor of medicine
NYU Grossman School of Medicine
MedicalResearch.com: How big is the problem of 
Dr. White[/caption]
Alexandra J. White, PhD, MSPH
Stadtman Investigator
Epidemiology Branch
National Institute of Environmental Health Sciences
National Institutes of Health
Research Triangle Park, NC
MedicalResearch.com: What is the background for this study? What is the chemical primarily used in hair straighteners?
Response: Hair products such as dye and chemical straighteners contain several different chemicals that may act as carcinogens or endocrine disruptors and thus may be important for cancer risk. Straighteners in particular have been found to include chemicals such as phthalates, parabens, cyclosiloxanes and metals and may release formaldehyde when heated. Previous research has suggested that hair dye and chemical straighteners are related to other hormone-sensitive cancers such as breast and ovarian cancer, but no previous study has considered how they are related to uterine cancer risk.
