Developing Better Medicine

Transcription

1 SURF 2013 Marietta L. Harrison, PhD Director, Oncological Sciences Center in Discovery Park Professor, Medicinal Chemistry and Molecular Pharmacology

2 How we do it today One size fits all Medicines aren t targeted to diseased tissues Doses aren t individualized - pediatric doses are often simply less than adult doses Medicines aren t tailored to individuals Where s the DNA?

3 The Era of Precision Medicine Giving the appropriate drug at the appropriate dose to the appropriate patient targeted to the diseased cells/tissues

4 The OMICS Revolution The quest for tests (biomarkers) to classify patients into subsets (appropriate drug to the appropriate patient) Cancer is an example of a major disease that is genetic in origin, which means that the fundamental causes and drivers of the disease are encoded in the DNA. changes in the DNA that cause disease can be inherited changes in the DNA that cause disease can be somatic somatic changes occur through the environment and aging process and are not present in sperm and egg DNA (inherited) patients with similar DNA changes are more alike than those with the same disease (e.g. colon cancer), but with different DNA changes patients with similar DNA changes should respond similarly to treatment

5 The OMICS Revolution The quest for biomarkers to classify patients into subsets Genomics -Genotype (SNPs, HapMap) -Gene Expression (mrnas) -Whole genome sequencing Metabolomics Proteomics -Protein Expression -Protein Modifications Lipidomics

6 Here are some Facts Jack!! DNA is Here to STAY DNA Will Lead the Way.. Human DNA encodes for more than 20,000 genes (located in the nucleus of cells) 3 billion base pairs in human DNA DNA in a single cell, stretched out, would cover 6 feet Humans and rhesus monkeys are 93% identical in their DNA sequences Humans and chimpanzees are 98.5% identical in their DNA sequences Human and humans are 99.5% identical in their DNA sequences

7 More Facts Jack!! DNA is Here to STAY DNA Will Lead the Way.. Genes are packaged as chromosomes -humans have 46 chromosomes or 23 pairs -chimpanzees have 48 chromosomes or 24 pairs -cows have 60 chromosomes or 30 pairs -bananas have 22 chromosomes or 11 pairs -fruit flies have 8 chromosomes or 4 pairs

8 DNA is Here to STAY DNA Will Lead the Way.. So if we are 99.5% identical, why do some of us respond to a given medicine and some of us do not? GOOD QUESTION!! And the answer is. SNPs (single nucleotide polymorphisms) SNPs are variations at a single base pair, or a single base pair substitution - ten million SNPS in human genome (but most are silent) - most changes in base pairs are passed down generation to generation - can tell how closely people are related by the number of SNPs they share

9 DNA is Here to STAY DNA Will Lead the Way.. So if SNPs are the answer why don t we make medicines that target individuals who have the same SNPs. They should all respond well to the targeted medicines. GOOD QUESTION!! And the answer is. Because we don t know which SNPs correlate with which types of diseases and we don t know which individuals have the same SNPs Need to identify biomarkers in DNA (and blood) that classify subsets of patients that share a commonality (SNPs and others) Need to design drugs and therapies targeted to subsets of patients who are predicted to respond Need to practice precision medicine

10 DNA Changes in Cancer More Facts Jack!! The vast majority of SNPs are inherited In cancer patients some SNPs are acquired from - the environment (cigarettes) - aging process - a lack of repair of damaged DNA

11 The OMICS Revolution Cancer as the Prime Example Genomics Proteomics BLOOD Lipidomics Finding a needle in a haystack Quadraspec Professors Regnier and Nolte Metabolomics GCGCMS PC Control 0.0 No Disease Cancer NMR PC Cancer NMR PC1 Biomatrix Professor Raftery

12 Integrated omics Analysis Genomics BLOOD Proteomics Lipidomics Molecular Signature of cancer Metabolomics No Disease Cancer

13 %Survival ( ) Why the hunt for biomarkers? Because Early Detection MATTERS Cancer Stage at Diagnosis Distant Regional Local 5 yrs Local 10 yrs Breast Colorectal Lung Prostate

14 Example of a Technique to Classify Cancers DNA Microarray Analysis (Gene Chips) Approximately 20,000 human genes Measures the relative amounts of all mrnas Detects changes between normal and cancer cells

15 DNA Microarray Analysis for Cancer Classify tumors into subtypes Predict which tumor subtypes will respond best to which anti-cancer drugs Predict which patients are likely to relapse using current drug treatments Identify targets for new drugs

16 DNA Microarray Analysis Diffuse Large B Cell Lymphoma (DLBCL) Five year survival rate is 52% DNA microarray analysis on leukemia cells from 52 DLBCL patients

17 DNA Microarray Analysis: Results Diffuse Large B Cell Lymphoma (DLBCL) DLBCL patients segregated into two groups (GC- B-like and B-like) based on the set of mrnas their cancer cells contained. GC-B-like patients had a five-year survival rate of 76%, while B-like had a five-year survival rate of 16%

18 DNA Sequencing: Future in Cancer Therapy Many more cancers will be sub-typed into different diseases. Cancers that today have an overall survival rate of less than 100% will be identified as two or more separate sub-types. Physicians will be able to predict which patients will respond to which treatments. Drug-therapy will be tailored to subsets of tumors based on the sets of biomarkers they contain, regardless of the tissue of origin. It will be possible to predict who is at high risk of developing life-threatening cancer.

19 Successes The OMICS Revolution Breast-cancer protein expression -EGFR (ERBB2/HER2/NEU)/ estrogen receptor + (trastuzumab/tamoxifen) Leukemia PML-RARA/CML: PhC translocation (all-trans retinonic acid/imatinib) CML: resistant to imatinib (Gleevec) and harboring distinct mutations in BCR-ABL (dasatinib and nilotinib) Lung-cancer EGFR mutations predict sensitivity to erlotinib or gefitinib -distinct K-Ras mutations predict failed treatment Distinct K-Ras mutations predict failed response to erlotinib or gefitinib in colon cancer Glioblastoma multiform mutations in EGFR predict response to erlotinib or gefitinib, but only in the presence of PTEN

20 The Future of Cancer Treatment Stratification of patients at diagnosis Increased predictive molecular signatures (biomarkers) for better therapeutic response Develop routine blood tests for early detection Identify molecular signatures to predict those at high risk Target potent anti-cancer drugs through nanomedicine

21 The Future: Engineering Better Medicines Nanomedicine Nanoparticles: teeny tiny, itsy bitsy, vessels Nanomedicines: drugs/agents delivered by nanoparticles Targeting molecule Potent drug So what s the big deal about Nanomedicine? nanoparticle Good Question!!! And the answer is.. The ability to target only diseased cells with concentrated, potent drugs that would be too toxic to use in an untargeted fashion.

22 The Future: Nanomedicines The Scale of Things Targeting molecule Potent drug nanoparticle nanometers 100,000 nanoparticles a single hair strand

23 Here are some Facts Jack!! The Future: Nanomedicine Currently over 250 nanomedicine products approved or in clinical development: - drugs (several diseases/conditions; tissue regeneration) - devices (implantable devices) - imaging agents Nano-vehicles for Cancer Treatment - 3 distinct nanoparticles in commercial use Engineered polymer-based nanoparticles (Bind-014) - allows precise, controlled formation of nanoparticles - all nanoparticles identical - specifically targeted to cancer cells - avoids detection and destruction by the immune system - controlled and slow drug release - tolerated side effects (toxicity)

24 The Language of Life: DNA and the Revolution in Personalized medicine Francis S. Collins Director: US National Human Genome Research Institute ( ) Director: NIH (2009-present)

25 SURF 2013 THANK YOU!!! Bought to you by.