Prostate Cancer Lab #26: Clinical Guidance from Proteomics (Sheeno Thyparambil)

A complete transcript is available at: https://cancerhackerlab.com/pr....ostate-cancer-lab-26

“When you go from DNA all the way to protein, we know there is a loss of information… All your drugs are actually acting against proteins, so the question becomes, should I measure the levels of protein to see what’s actually expressed, whether through mass spectrometry or through immunohistochemistry…? That would be super helpful.” – Sheeno Thyparambil
Meeting Summary
Most cancer patients these days get a genomic analysis (DNA sequencing) of their tumor tissue. Some get translational analysis (RNA sequencing), even though few oncologists may know how to interpret the RNA results. Few patients get proteomic analysis, so most are missing this opportunity for additional treatment guidance. There are biomarkers that can be identified through proteomic analysis, such as HER2, that can point to targeted drugs with better patient outcomes than standard treatments.
Depending on genomics analysis alone to guide treatment can introduce errors. When you go from DNA to RNA to protein, how much information is lost? When you go from DNA to RNA, let’s say 50% of your information is transmitted. And then from RNA to protein, maybe 30% of the information is translated. So, when you go from DNA to proteins (gene expression), we know there is a loss of information. Yet all drugs are acting against proteins: should I measure the levels of proteins to see what’s actually being expressed, either through mass spectrometry or immunohistochemistry, to know if the proteins are being expressed?
Dr. Sheeno Thyparambil is the Senior Director (R&D) of the mProbe Precision Oncology division. He has extensive experience in developing and deploying clinical diagnostics products, especially the use of mass spectrometry for clinical tests. He describes how mass spectrometry-based clinical proteomics can guide treatment decisions, providing arguments advanced cancer patients can use with their oncologists to liberate some of their tissue (FFPE) for this test.
A main reason why a lot of oncologists and patients are interested in mass spectrometry-derived proteomic tests is helping with chemotherapy decisions. Many tests help inform targeted therapy decisions, or whether you need chemo or not, but few help decide what type of chemo regimen to choose. For example, mass spectrometry-derived protein biomarker reports will say, “This patient is likely to respond to some chemotherapies, like epirubicin or doxorubicin, or they will have a resistance to other drugs, such as a cisplatin- or oxaliplatin-based drug.”
For targeted therapy, the most popular protein biomarkers are HER2 (human epidermal growth factor receptor 2, an important protein in breast and gastric cancer) and PDL1 (programmed death ligand-1, a protein that helps keep immune cells from attacking non-harmful cells in the body), but there are others, especially for prostate cancer, such as AR TROP2 (androgen receptor trophoblast cell-surface antigen-2, an important target for antibody-drug conjugates), which point to new drugs.
Proteomic identification of biomarkers can also steer treatment to a clinical trial. Example: a patient showed a very high level of a biomarker (MET, mesenchymal epithelial transition factor receptor), then after a round of chemotherapy, the biomarker jumped. The oncologist decided to switch the patient’s treatment to a phase one clinical trial targeted on the biomarker, which was very successful.

00:00:00 Meeting Introduction
00:02:34 Clinical Guidance from Proteomics
00:04:02 History
00:05:42 Central Dogma
00:06:02 Targeted Clinical Proteomics Workflow
00:10:33 Protein Identification & Quantitation Using Targeted Proteomics
00:10:51 Technical Summary
00:11:31 Oncologist Treatment Options
00:12:41 Biomarker Assays Run in the CAP/CLIA Lab
00:15:05 Management of Advanced Gastroesophageal Cancer
00:16:41 Cancer Types Assayed
00:17:37 Salivary Duct Carcinoma
00:18:13 Longitudinal Follow-up: Gastric Cancer
00:19:09 Gastric linitis plastica
00:19:18 Gastric/gastroesophogeal Junction
00:20:18 Pancreatic Cancer
00:21:37 Biomarker Analysis
00:21:57 Treatment Protocol and Outcome
00:22:12 Case Report: Glioblastoma
00:23:22 R&D
00:23:31 Select Publications
00:23:52 Quantitative Her2 Proteins Levels Across Different IHC Levels
00:25:42 Identification of Durable Responders to Anti-Her2 Therapy
00:26:56 Trastuzumab Deruxtecan (T-DxD) Approval in Low Her2 Breast Cancer
00:26:21 Quantitative Her2 Proteins Levels Across Different IHC Levels
00:27:43 HER2 Levels in Prostate Cancer
00:29:10 Antibody-Drug Conjugate
00:30:21 ADC Biomarkers: Measure Both Receptor and Payload Biomarkers
00:33:00 Expression Distribution of TROP2 and Payload Targets ...
00:35:32 Trop2 ADC Clinical Trial
00:38:41 Central Dogma: Loss of Information
00:40:57 Our Collaborators
00:41:08 Acknowledgments
00:41:58 More Information
00:42:30 Q&A

• Category

  Pancreatic Cancer