Combination Therapies


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a look into the current state of combination therapies

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  • Need to not only find different molecular patterns, but you have to be able to know the signaling patterns to properly predict and devise a therapeutic regiment!! For instance, an inhibitor to an oncogene may be under-expressed .. Hence attacking the over-expressed oncogene wont matter.
  • Source: Molecular differences even within the same person in the case of cancer!!
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  • Cancer refers to the uncontrollable growth of cells. This arises from an over-expression of what are called oncogenes, and an under-expression of what are called tumor suppressors. You can think of oncogenes as a GREEN light for cells to grow (their definition is any protein/enzyme that, when normally expressed, promotes cell growth), and tumor suppressors as a RED light (they are any enzyme/protein that, when normally expressed, suppresses or stops cell growth). There are many, many oncogenes and tumor suppressors in the cell, very often working at the same time. “ EGFR” is a growth receptor / oncoprotein (remember genes code for proteins) that is often over-expressed in tumors. There is a therapy known as Tarceva that inhibits EGFR proteins from functioning by binding to that protein’s energy source – it’s ATP binding site. However, an over-expression of “MET” – another oncoprotein, is associated with RESISTANCE to Tarceva. This means that if you have an over-expression of MET and EGFR, then Tarceva will NOT be beneficial to you. This dynamic concept illustrates why it is important to know the molecular profile of the diseased cells in the body to see if they express MET and EGFR or if they just over-express EGFR when deciding treatment options. Another Example: Xeloda + TP overexpression = good, but Xeloda + thymidylate synthase overexpression = bad.;
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  • FUS1, MDM2, P53 Therapy : This is going to get very tough to follow so be careful. P53 is a “stopper” of cell growth. It is a very often knocked out (inactive or missing) in tumor cells. MDM2 is an inhibitory protein of p53 (so it’s a promoter of cell growth – an oncoprotein). FUS1 is an inhibitor of MDM2, which inhibits p53, thus FUS1 is a stopper of cell growth (tumor suppressor). Application Let’s say, you took a sample of someone’s tumor and it showed an overexpression of MDM2; however, you didn’t test for other mutations/expression levels. You then gave that person MDM2 antibodies / inactivators as a treatment. The problem here with this is, if this tumor cell also has a mutated, inactive p53 gene, then blocking the action of this inhibitory protein makes no difference because p53 will still be inactive. This illustrates the need to test for various proteins in these known signaling pathways to realize the most effective benefits of a therapy. It is important to note here that every protein has another promoter/inhibitor molecule regulating it. Each of these regulating proteins are coded by a cell’s DNA. The signaling pathways within cells has taken decades to understand and is still far from fully being understood. However, there are known signaling pathways that we can test patients for particular discrepancies in – enhancing the effectiveness and safety of therapeutic effects on patients. As well, if a database were to be collected and everyone were to undergo this “sequencing” and testing of proteins/genes, then we could isolate the causes of rare side effects.
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  • Source: wiki, clinical trials
  • Combination Therapies

    1. 1. Combination Therapies: the promise to cure… everything ? By I&C President Ryan Witt [email_address]
    2. 2. Cure everything???!? <ul><li>Cancer </li></ul><ul><li>Cardiovascular disease </li></ul><ul><li>Alzheimer’s Disease </li></ul><ul><li>Bacterial Infections </li></ul><ul><li>Yes. I’ll Explain. </li></ul><ul><li>ALS </li></ul><ul><li>Multiple Sclerosis </li></ul><ul><li>HIV/AIDS </li></ul><ul><li>Hepatitis </li></ul>
    3. 3. But, Remember <ul><li>Ask Q s! </li></ul><ul><li>Always ask “How, Why, What, and When” </li></ul><ul><li>Try to Understand EVERYTHING! </li></ul>
    4. 4. Concept <ul><li>With a knowledge -based approach, what can we do? </li></ul>
    5. 5. Knowledge we need <ul><li>Nearly every drug approved on the market, by a regulatory agency, has a known molecular mode of action . </li></ul><ul><li>If you distinguish the molecular characteristics of a disease from a “normal” cell’s characteristics, you can then match drugs with that disease and known molecular signaling pathways within a disease ! </li></ul><ul><li>This is the idea fueling (i) “Combination Therapies” and (ii) “Drug Repositioning” </li></ul>
    6. 6. Current Treatment (Rx) and Drug Development Protocols for Diseases <ul><li>Past: Age of One Drug Wonders </li></ul><ul><ul><li>Penicillin – bacteria </li></ul></ul><ul><li>Now we face tougher problems… </li></ul><ul><li>Multigenetic diseases – cancer, Alzheimer’s and Parkinson’s diseases, cardiovascular disease, MS, HIV / viruses… </li></ul><ul><li>Disease Resistance </li></ul><ul><ul><li>Infectious Diseases </li></ul></ul><ul><ul><li>HIV </li></ul></ul><ul><ul><li>Cancer </li></ul></ul>
    7. 7. Disease Complexity / Multigeneity <ul><li>Cancer has been called hundreds of sub-diseases; reason is because it results from multiple diff’t molecular dysfunctions. </li></ul><ul><li>Molecular Signaling within cells is highly complex. </li></ul>
    8. 8. Disease Resistance <ul><li>Arises from </li></ul><ul><li>Not fully killing the diseased cells and/or </li></ul><ul><li>Some degree of adaptive “randomness” in the disease; and </li></ul><ul><li>“ Selection” to grow those diseased cells who were not killed or are more adept. </li></ul><ul><li>With Cancer and HIV: the molecular systems driving these diseases are constantly changing due to high mutation and growth rates. (they adapt!) </li></ul>
    9. 9. Resistance Development within One Cell <ul><li>“ Window of Opportunity” with diseases where you can strike based on armaments available, and strike HARD! </li></ul><ul><li>PARP up-regulated after chemotherapy, if missing DNA repair enzymes of BRCA and PTEN family. </li></ul><ul><li>As you see later, cocktail could be better! </li></ul>Cancer upregulates PARP (another DNA repairman), thus defending itself against too much DNA damage. Cancer w. dysfunctional PTEN Chemo Chemo mutates DNA of cells to kill them! Cancer w. dysfunctional PTEN PARP-1
    10. 10. What is a combination therapy? <ul><li>The combination of two or more separate components – be it drugs, medical devices, or biological products (a substance derived from a living organism), for the purpose of some end-goal. </li></ul><ul><li>Goal </li></ul><ul><li>Big attack – not in size but strength </li></ul><ul><li>Localized attack </li></ul>
    11. 11. Concept <ul><li>It’s better to fight something with two or more small attacks specific (molecularly) to a target, both in effectiveness and safety, when compared to one single massive attack. </li></ul><ul><li>i.e., Nuke v. Targeted Assassinations </li></ul><ul><li>Support from Studies (all entering or in clinical validation testing now): </li></ul><ul><li>Cocktail against brain tumors </li></ul><ul><li>MET / EGFR cocktail – more on this later </li></ul><ul><li>Chemo targeted to liver, avoiding adverse effects to heart </li></ul><ul><li>HIV Cocktail – Atripla (*approved) </li></ul><ul><li>Cocktail against Alzheimer’s Disease </li></ul>
    12. 12. The Benefits <ul><li>Greater effectiveness on disease target </li></ul><ul><li>Lower side effects on host (me and you) </li></ul><ul><li>Lower chance of resistance development (from disease) </li></ul>
    13. 13. Theoretical Examples: applying the concept <ul><li>Cancer </li></ul><ul><li>Other studies where relevance is shown </li></ul><ul><li>MS </li></ul><ul><li>ALS </li></ul><ul><li>Alzheimer’s </li></ul><ul><li>Parkinson’s </li></ul><ul><li>HIV </li></ul><ul><li>Infectious diseases (viruses/bacteria) </li></ul><ul><li>Hepatitis B recurrent in post liver transplant & Hepatitis C </li></ul>
    14. 14. Cancer <ul><li>EGFR & MET therapy (on its way to clinical studies now) </li></ul><ul><li>FUS1 , MDM2 , & P53 therapy (tested separately in clinical trial) </li></ul><ul><li>PARP + Chemo – breast and ovarian cancer (in clinical trail now) </li></ul><ul><li>Brain Tumors – 3 proteins targeted (on its way to clinical studies) </li></ul>
    15. 15. EGFR & MET <ul><li>“ Our findings provide a strong rationale for combination treatment strategies as initial therapies for some patients.” - Pasi Jänne MD, PhD, of Dana-Faber Cancer Institute and Associate Professor of Medicine at Harvard Medical School </li></ul><ul><li>Status: expected to move into clinical study soon </li></ul>Source: EGFRi Tarceva / Iressa HGF cancer cancer cancer GAB1 + cancer cancer cancer cancer cancer MET EGFR METi Tumor Response
    16. 16. FUS1 , MDM2 , & P53 therapy Tested in clinical trials separately.
    17. 17. PARP inhibitors & Chemo <ul><li>Being tested in clinical trial now, with “very promising results.” – Medscape article </li></ul>PTEN + BRCA 1/2 + PARP = DNA Repairmen When no PTEN (or BRCA1/2), PARP is active/over-expressed, especially in cancers after undergoing chemotherapy. Idea for Cancer Therapy is giving PARP inhibitors to people who have already undergone chemotherapy to prevent this defense mechanism OR PARP inhibitors, with chemo, as a first line treatment. This makes sense b/c cancer cells don’t want to be mutated and die from the chemotherapy, thus defend themselves through upregulating PARPs (repairmen) when they don’t have PTEN or BRCA proteins. Sources:;;
    18. 18. Brain tumors <ul><li>Interleukin 13 receptor alpha 2 (IL-13R-alpha), </li></ul><ul><li>Ephrin receptor A2 (EphA2) </li></ul><ul><li>Fos-related antigen 1 (Fra-1) </li></ul><ul><li>Among 76 patients with brain tumors, all with GBMs had one marker present and 95% had at least two of these markers. </li></ul><ul><li>“ The three markers were not found in healthy brain tissue, suggesting that the proteins are highly suited as targets for therapies designed to kill cancer cells and spare healthy brain tissue.” </li></ul>Source:
    19. 19. A few quotes <ul><li>“ This is why it's so important to be able to use a combination of more than one drug. If the virus mutates to become resistant to one drug, it is still sensitive to the other drugs .” </li></ul><ul><ul><ul><li>- Genhong Cheng, Research team member at the UCLA Center for Cell Control and UCLA's Jonsson Comprehensive Cancer Center </li></ul></ul></ul><ul><li>“ Drug combinations can also be used effectively to inhibit infectious diseases because resistance to a single drug is very common… If we can apply multiple drugs against one infectious agent, it probably will prevent the occurrence of drug resistance.” </li></ul><ul><ul><ul><li>Ren Sun, UCLA Professor of Molecular and Medical Pharmacology and research team member </li></ul></ul></ul><ul><li>From a study finding that total inhibition of a virus occurred at much lower drug doses than would be necessary if the drugs were used alone (~10% less than required when each drug is adminstered individually) </li></ul>
    20. 20. But, remember <ul><li>Always ask: Why, How, What, and WHEN </li></ul><ul><li>Any Questions? </li></ul>
    21. 21. Ex of Cocktails Approved <ul><li>Only one approved cocktail comes to mind – </li></ul><ul><ul><li>HIV, there is now one “cocktail” pill you can take which includes all three primary therapies for the disease. </li></ul></ul><ul><ul><ul><li>Approved post approval of each individual component. </li></ul></ul></ul><ul><ul><li>Combo, chemotherapies + monoclonal Antibodies like Herceptin / EGFR targets </li></ul></ul><ul><ul><ul><li>Approved after testing one experimental therapy in combo with already approved chemo drugs. </li></ul></ul></ul>
    22. 22. When <ul><li>When matters! </li></ul><ul><ul><ul><li>If you don’t get why after these next few slides, stop me in my tracks!! </li></ul></ul></ul>
    23. 23. Importance of Timing in the Development of Combo-Therapies <ul><li>Physician Developed </li></ul><ul><li>Two or more approved therapies </li></ul><ul><ul><li>Dosage and interactions are untested! </li></ul></ul><ul><ul><li>Possibly can try to predict dosage/interactions </li></ul></ul><ul><li>Pharma Development by testing </li></ul><ul><li>An approved therapy with (i) an investigational or (ii) another approved therapy </li></ul><ul><ul><li>Avg time for development – 14 years for a cancer therapy! </li></ul></ul><ul><ul><li>Many pharmas know now of possible combo benefits, but test each drug one at a time anyway.. </li></ul></ul><ul><li>Combo of two investigational therapies </li></ul><ul><ul><li>Never happened to my knowledge </li></ul></ul>
    24. 24. Problems with Physician Developed Combinations <ul><li>Each individual component is tested for max tolerable dose… </li></ul><ul><ul><li>Hence, when combining two or more drugs, physicians have no idea what dose to give patients </li></ul></ul><ul><li>Also: potential interactions between drugs are unknown. </li></ul>
    25. 25. Innovation in the Works <ul><li>The development of cocktails from pharmas (where dosage and safety are tested prior to administration to patients) </li></ul><ul><li>Drug repositioning </li></ul><ul><li>But, for now </li></ul><ul><li> </li></ul>
    26. 26. Combination Rxs Used Now <ul><li>Combination therapies are primarily created by physicians through “off-label use” or already approved chemotherapy-combo regimens. </li></ul>
    27. 27. What to do? <ul><li>Ask your physician about being treated with a potent, specific regimen–targeted to your disease–especially, if you are dealing with a seriously compromising illness. </li></ul><ul><li>Ask your doc Qs: “How, what, why, and when?” </li></ul>
    28. 28. What is I&C Doing? <ul><li>Bringing innovation to you at the fastest rate possible is our goal. </li></ul><ul><li>Community-based education and resource sharing </li></ul><ul><li>Building an interface to empower you to make a difference </li></ul><ul><li>Working to integrate these innovations and patient options into physicians’ workflow. </li></ul>
    29. 29. Combination Therapy Resources <ul><li>Targeted Drug Delivery Tool </li></ul><ul><ul><li>IsoFlow </li></ul></ul><ul><ul><li>Ultrasound released therapy (untested in humans) </li></ul></ul><ul><ul><li>UV activated therapy (untested in humans) </li></ul></ul><ul><li>Drug repositioning / finding for your disease </li></ul><ul><ul><li>GeneGo – Metacore </li></ul></ul><ul><ul><li>Biovista </li></ul></ul><ul><li>Targeted approach specifically for cancer– </li></ul><ul><ul><li>N-of-One </li></ul></ul><ul><ul><li>Intervention Insights / GeneGo </li></ul></ul><ul><ul><li>ICAN </li></ul></ul>