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University of Maryland Baltimore
Experimental Therapeutics Symposium 2009

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  1. 1. Update on P30 and Chemotherapy Neuropathy Studies Susan G. Dorsey PhD RN Associate Professor
  2. 2. UMB CENTER FOR PAIN STUDIES PI/Director: Susan G. Dorsey Associate Director: Deborah B. McGuire P30 NR011396-01 NIH/NINR $2,400,000 08/07/2009-05/31/2014 UMSON UMSON UMSOM UMSON UMSOD JOAN DAVENPORT PhD RN Clinical study of mucositis pain Mentor: Deborah B. McGuire KATHLEEN GRIFFITH PhD RN Clinical study of chemotherapy-induced peripheral neuropathy pain Mentor: Deborah A. Sherman NAIMISH PANDYA MD Clinical study of chemotherapy-induced peripheral neuropathy pain Mentor: Susan G. Dorsey NILOOFAR REZVANI PhD Animal study of chemotherapy-induced mucositis pain Mentor: Sharon Gordon/Rich Traub CYNTHIA RENN PhD RN Animal study of chemotherapy- induced peripheral neuropathy pain Mentor: Susan G. Dorsey/Chris Ward P30 Pilot Studies: BIOBEHAVIORAL CORE Director: Joel Greenspan Co-Directors: Christopher Ward Richard Traub BIOSTATISTICS CORE Director: Yulan Liang Co-Director: Hong-Bin Fang GENETICS CORE Director: Nick Ambulos Co-Director: Jing Yin P30 Cores:
  3. 3. Aromatase-induced Arthralgia Animal Model Development <ul><li>Collaborators </li></ul><ul><ul><li>Angela Brodie </li></ul></ul><ul><ul><li>Sara Chumsri </li></ul></ul><ul><ul><li>Ting Bao </li></ul></ul><ul><ul><li>Cynthia Renn </li></ul></ul><ul><ul><li>Christopher Ward </li></ul></ul><ul><li>Funding </li></ul><ul><ul><li>P30 pilot grant for equipment purchase </li></ul></ul>
  4. 4. AI Arthralgia and Arthritis <ul><li>Occurs in 20-40% of postmenopausal breast cancer patients treated with AIs (Anastrozole, Tamoxifen, Alone or in Combination [ATAC] trial) </li></ul><ul><li>Most significant risk factors </li></ul><ul><ul><li>Previous HRT, previous chemotherapy, North American, BMI > 30 (Sestak et al Lancet Oncol 2008; 9:866) </li></ul></ul><ul><ul><li>Previous taxane, BMI 25-30 (Crew et al JCO 2007; 9:3877) </li></ul></ul><ul><li>5-10% of patients discontinue AI treatment due to severity of symptoms </li></ul><ul><li>Mechanisms poorly understood; conventional pain medications are not effective </li></ul><ul><li>To date, no published animal model </li></ul>
  5. 5. A Xenograft Model for Hormone Dependent Breast Cancer in Postmenopausal Patients Aromatase-transfected MCF-7Ca (2.5x10 6 cells/site), s.c.  4A (100  g/day), s.c. Duration of the experiment Estrogens are produced locally by the aromatization of androstenedione (  4A) TUMORS ARE SENSITIVE TO BOTH ANTIESTROGENS AND AROMATASE INHIBITORS Ovariectomized
  6. 6. Fore-paw grip strength in the mouse <ul><li>Sensitive assay of motor neuron and muscle dysfunction in mice. </li></ul><ul><li>The maximal value (in g) of 5 successive trials (15 s rest) </li></ul><ul><li>Top three values are averaged and normalized to bodyweight (g) </li></ul>
  7. 7. Fore-paw grip strength in the AI treated tumor bearing mouse
  8. 8. *
  9. 9. Heat Thresholds
  10. 10. Cold Thresholds ** * ** *
  11. 11. Future experiments <ul><li>Continue to follow until study endpoint </li></ul><ul><li>At study endpoint </li></ul><ul><ul><li>Image tendon integrity </li></ul></ul><ul><ul><li>Isolate hindlimb muscles and measure contractility in vitro </li></ul></ul><ul><ul><li>Examine molecular and genetic changes in DRG and spinal dorsal horn </li></ul></ul>
  12. 12. Oxaliplatin-induced Neuropathy Animal Model Studies <ul><li>P30 Pilot PI </li></ul><ul><ul><li>Cynthia L. Renn </li></ul></ul><ul><li>Funding </li></ul><ul><ul><li>P30 pilot grant years 1-3 </li></ul></ul>
  13. 13. Chemotherapy-induced Neuropathy <ul><li>Most common treatment-related complication associated with taxane, platinum and vinca alkaloid regimens </li></ul><ul><li>Neuropathic symptoms include numbness, tingling, lancinating pain </li></ul><ul><li>Oxaliplatin unique in that acute neurotoxicity triggered by cold occurs during/after infusion in 95% of patients </li></ul><ul><li>Chronic neurotoxicity produces sensory dysfunction and occurs in 10-20% of patients </li></ul>
  14. 14. Study Protocol <ul><li>Generate animal model of oxaliplatin-induced neuropathy </li></ul><ul><li>Examine gene expression changes at timepoints when behavioral changes are most robust in DRG and SDH </li></ul><ul><li>Intervene with exercise and pathway agonists/antagonists in dorsal horn and brainstem </li></ul>
  15. 18. <ul><li>Collaborators </li></ul><ul><ul><li>Nancy Gambill (co-PI) </li></ul></ul><ul><ul><li>Darren Couture/Erika Glass </li></ul></ul><ul><ul><li>Naimish Pandya </li></ul></ul><ul><ul><li>Sharon Gordon </li></ul></ul><ul><ul><li>Raymond Dionne </li></ul></ul><ul><ul><li>Todd Milliron </li></ul></ul><ul><ul><li>Amada Mason </li></ul></ul><ul><ul><li>Theresa Johnston </li></ul></ul><ul><ul><li>Lori Tanguay </li></ul></ul><ul><ul><li>Mary Quinn </li></ul></ul><ul><li>Funding </li></ul><ul><li>Bench to Bedside 3R01NR010207-02S1 07/01/08-03/31/10 $290,130 </li></ul><ul><li>UMSON/UMMC Seed Grant </li></ul>Clinical Study: Sensory Fiber Changes after Chemotherapy (0852GCC/P-00040725)
  16. 19. Overview <ul><li>Goal – determine whether we can identify sensory fiber changes prior to patient report of symptoms. </li></ul><ul><li>Subjects/Inclusion Criteria – </li></ul><ul><ul><li>Solid tumor (protocol target accrual N=35) </li></ul></ul><ul><ul><li>Chemotherapy naïve (neurotoxic) </li></ul></ul><ul><ul><li>Scheduled to receive taxane, platinum or vinca alkaloid </li></ul></ul><ul><ul><li>English speaking </li></ul></ul><ul><ul><li>21-64 years of age (may increase age) </li></ul></ul><ul><ul><li>Written informed consent </li></ul></ul>
  17. 20. Study Protocol <ul><li>Design – prospective descriptive study </li></ul><ul><ul><li>Measurements at baseline and then at every infusion visit. Study endpoint is dose-limiting neurotoxicity or 6 months. </li></ul></ul><ul><li>Measures – </li></ul><ul><ul><li>FACT-GOG NTx (38 item-physical, social, emotional, functional well-being plus additional concerns neuropathic) </li></ul></ul><ul><ul><li>Neuropathic Pain Scale (10 item) </li></ul></ul><ul><ul><li>NCI-CTC v3.0 August 9, 2006 </li></ul></ul><ul><ul><li>Thermal and Pain Thresholds (cold, warm, mechanical, vibration, pin prick) </li></ul></ul><ul><ul><li>Grip strength/DTR </li></ul></ul><ul><ul><li>Skin biopsy (RNA extraction and axon quantification) </li></ul></ul><ul><ul><li>Serum samples (RNA and DNA extraction) </li></ul></ul>
  18. 21. *Serum collection baseline and then every 21 days and at study endpoint *Skin biopsy at baseline and then at time of neuropathy development (dose-limiting) or study endpoint
  19. 22. Eligibility Screening <ul><li>Protocol active since June 2009; screening initiated in August 2009 </li></ul><ul><li>To date, we have screened 433 GCC patients </li></ul><ul><ul><li>96.8% (n=419) English speaking </li></ul></ul><ul><ul><li>72.1% (n=312) met age criteria </li></ul></ul><ul><ul><li>67.2% (n=291) solid tumor dx </li></ul></ul><ul><ul><li>30.5% (n=132) chemo naïve </li></ul></ul><ul><ul><li>17.8% (n=77) receiving T/P/V </li></ul></ul>
  20. 23. Enrolled Subjects <ul><li>Enrolled n=2 (as of 29 September 2009) </li></ul><ul><ul><li>56 yo female with small-cell lung cancer receiving cisplatin (108-110mg) every 3 weeks (On study 08/31/2009 baseline; one f/u visit 09/21/2009) </li></ul></ul><ul><ul><li>63yo male with tongue squamous cell carcinoma to start receiving cisplatin </li></ul></ul><ul><li>Of those eligible, n=2 refused to enroll; 1 enrolled but could not participate in another trial so de-enrolled </li></ul><ul><li>Five were eligible except for age (Modification under review to increase age eligibility) </li></ul><ul><li>Four new patients for screening in the next week </li></ul>