Program Official

Principal Investigator

Patrick M
Dougherty
Awardee Organization

University Of Tx Md Anderson Can Ctr
United States

Fiscal Year
2020
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

The role of ENF loss, TLR4 and spinal plasticity in paclitaxel CIPN

Peripheral neuropathy is the principal dose-limiting factor for each of the major frontline chemotherapeutic drugs used against all the most common types of cancer and hence affects hundreds of thousands of patients each year. Neuropathy causes such distress that many patients will drop out of potentially curative therapy, directly impacting their survival. Chemotherapy-induced peripheral neuropathy (CIPN) is refractory to treatment and often persists in cancer survivors limiting quality of life, rehabilitation and the return to productivity. The continuing long-term goal of this project is to determine the mechanisms of CIPN and identify potential therapeutic interventions for its relief or prevention. The main hypothesis in this project is that chemotherapeutics activate toll-like receptor 4 (TLR4) on subsets of DRG neurons that 1) trigger altered cellular signaling in DRG neurons and infiltration of the DRG by immune cells that initiate and sustain CIPN; 2) drive the loss of distal epidermal nerve fibers (ENFs) to a critical point associated with onset of CIPN symptoms; and 3) cause activation of spinal glia and neurons that result in maladaptive changes in the physiology of these cells that further contribute to CIPN symptoms. This hypothesis will be tested in humans and animals that receive chemotherapy treatments. Specific Aim 1 will determine whether activation of innate immunity in the DRG is a key initiating step in CIPN. Specific Aim 2 will determine whether CIPN in humans is triggered when peripheral innervation density decreases to a critical point during chemotherapy. Specific Aim 3 will determine the role of TLR4 and damage associated molecular pattern (DAMP) proteins in driving maladaptive plasticity in the spinal dorsal horn contributing to CIPN. In summary this project will define mechanisms of chemotherapy-induced peripheral neuropathy, identify patient risk factors and potential new near-term protective and treatment candidates. This project will therefore impact on the quality of life, survival and the return to productivity of thousands of cancer patients.

Publications

  • Amit M, Takahashi H, Dragomir MP, Lindemann A, Gleber-Netto FO, Pickering CR, Anfossi S, Osman AA, Cai Y, Wang R, Knutsen E, Shimizu M, Ivan C, Rao X, Wang J, Silverman DA, Tam S, Zhao M, Caulin C, Zinger A, Tasciotti E, Dougherty PM, El-Naggar A, Calin GA, Myers JN. Loss of p53 drives neuron reprogramming in head and neck cancer. Nature. 2020 Feb;578(7795):449-454. Epub 2020 Feb 12. PMID: 32051587
  • Trahan LH, Cox-Martin E, Johnson CE, Dougherty PM, Yu J, Feng L, Cook C, Novy DM. Psychometric Study of the Pain Drawing. Journal of applied biobehavioral research. 2017 Dec;22. (4). Epub 2017 Apr 7. PMID: 29230086
  • Hibino H, Gorniak SL. Effects of aging on rapid grip force responses during bimanual manipulation of an active object. Experimental brain research. 2020 Oct;238(10):2161-2178. Epub 2020 Jul 13. PMID: 32661648
  • Middleton SJ, Barry AM, Comini M, Li Y, Ray PR, Shiers S, Themistocleous AC, Uhelski ML, Yang X, Dougherty PM, Price TJ, Bennett DL. Studying human nociceptors: from fundamentals to clinic. Brain : a journal of neurology. 2021 Jun 22;144(5):1312-1335. PMID: 34128530
  • Paice JA, Mulvey M, Bennett M, Dougherty PM, Farrar JT, Mantyh PW, Miaskowski C, Schmidt B, Smith TJ. AAPT Diagnostic Criteria for Chronic Cancer Pain Conditions. The journal of pain. 2017 Mar;18(3):233-246. Epub 2016 Nov 21. PMID: 27884691
  • Baruch EN, Nagarajan P, Gleber-Netto FO, Rao X, Xie T, Akhter S, Adewale A, Shajedul I, Mattson BJ, Ferrarotto R, Wong MK, Davies MA, Jindal S, Basu S, Harwood C, Leigh I, Ajami N, Futreal A, Castillo M, Gunaratne P, Goepfert RP, Khushalani N, Wang J, Watowich S, Calin GA, Migden MR, Vermeer P, D'Silva N, Yaniv D, Burks JK, Gomez J, Dougherty PM, Tsai KY, Allison JP, Sharma P, Wargo J, Myers JN, Gross ND, Amit M. Inflammation induced by tumor-associated nerves promotes resistance to anti-PD-1 therapy in cancer patients and is targetable by interleukin-6 blockade. Research square. 2023 Jul 18. PMID: 37503252
  • Abdi S, Dougherty PM. Chemotherapy-Induced Peripheral Neuropathy: A Challenge for Clinicians. Oncology (Williston Park, N.Y.). 2016 Nov 15;30(11):1030, C3. PMID: 27854105
  • Zhang H, Li Y, de Carvalho-Barbosa M, Kavelaars A, Heijnen CJ, Albrecht PJ, Dougherty PM. Dorsal Root Ganglion Infiltration by Macrophages Contributes to Paclitaxel Chemotherapy-Induced Peripheral Neuropathy. The journal of pain. 2016 Jul;17(7):775-86. Epub 2016 Mar 12. PMID: 26979998
  • Vedantam A, Bruera E, Hess KR, Dougherty PM, Viswanathan A. Somatotopy and Organization of Spinothalamic Tracts in the Human Cervical Spinal Cord. Neurosurgery. 2019 Jun 1;84(6):E311-E317. PMID: 30011044
  • Gewandter JS, Brell J, Cavaletti G, Dougherty PM, Evans S, Howie L, McDermott MP, O'Mara A, Smith AG, Dastros-Pitei D, Gauthier LR, Haroutounian S, Jarpe M, Katz NP, Loprinzi C, Richardson P, Lavoie-Smith EM, Wen PY, Turk DC, Dworkin RH, Freeman R. Trial designs for chemotherapy-induced peripheral neuropathy prevention: ACTTION recommendations. Neurology. 2018 Aug 28;91(9):403-413. Epub 2018 Jul 27. PMID: 30054438
  • Dougherty PM, Chen J. Relationship of membrane properties, spike burst responses, laminar location, and functional class of dorsal horn neurons recorded in vitro. Journal of neurophysiology. 2016 Sep 1;116(3):1137-51. Epub 2016 Jun 22. PMID: 27334950
  • Roldan CJ, Johnson C, Lee SO, Peng A, Dougherty PM, Huh B. Subclinical Peripheral Neuropathy in Patients with Head and Neck Cancer: A Quantitative Sensory Testing (QST) Study. Pain physician. 2018 Jul;21(4):E419-E427. PMID: 30045608
  • Krukowski K, Eijkelkamp N, Laumet G, Hack CE, Li Y, Dougherty PM, Heijnen CJ, Kavelaars A. CD8+ T Cells and Endogenous IL-10 Are Required for Resolution of Chemotherapy-Induced Neuropathic Pain. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2016 Oct 26;36(43):11074-11083. PMID: 27798187
  • Wang XS, Shi Q, Dougherty PM, Eng C, Mendoza TR, Williams LA, Fogelman DR, Cleeland CS. Prechemotherapy Touch Sensation Deficits Predict Oxaliplatin-Induced Neuropathy in Patients with Colorectal Cancer. Oncology. 2016;90(3):127-35. Epub 2016 Feb 17. PMID: 26882477
  • Vedantam A, Hou P, Chi TL, Hess KR, Dougherty PM, Bruera E, Viswanathan A. Postoperative MRI Evaluation of a Radiofrequency Cordotomy Lesion for Intractable Cancer Pain. AJNR. American journal of neuroradiology. 2017 Apr;38(4):835-839. Epub 2017 Feb 16. PMID: 28209581
  • Boyette-Davis JA, Hou S, Abdi S, Dougherty PM. An updated understanding of the mechanisms involved in chemotherapy-induced neuropathy. Pain management. 2018 Sep 1;8(5):363-375. Epub 2018 Sep 13. PMID: 30212277
  • Cox-Martin E, Trahan LH, Cox MG, Dougherty PM, Lai EA, Novy DM. Disease burden and pain in obese cancer patients with chemotherapy-induced peripheral neuropathy. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2017 Jun;25(6):1873-1879. Epub 2017 Jan 26. PMID: 28124735
  • Ma J, Kavelaars A, Dougherty PM, Heijnen CJ. Beyond symptomatic relief for chemotherapy-induced peripheral neuropathy: Targeting the source. Cancer. 2018 Jun 1;124(11):2289-2298. Epub 2018 Feb 20. PMID: 29461625
  • North RY, Odem MA, Li Y, Tatsui CE, Cassidy RM, Dougherty PM, Walters ET. Electrophysiological Alterations Driving Pain-Associated Spontaneous Activity in Human Sensory Neuron Somata Parallel Alterations Described in Spontaneously Active Rodent Nociceptors. The journal of pain. 2022 Aug;23(8):1343-1357. Epub 2022 Mar 12. PMID: 35292377
  • Uhelski ML, Li Y, Fonseca MM, Romero-Snadoval EA, Dougherty PM. Role of innate immunity in chemotherapy-induced peripheral neuropathy. Neuroscience letters. 2021 Jun 11;755:135941. Epub 2021 May 4. PMID: 33961945
  • Li Y, North RY, Rhines LD, Tatsui CE, Rao G, Edwards DD, Cassidy RM, Harrison DS, Johansson CA, Zhang H, Dougherty PM. DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2018 Jan 31;38(5):1124-1136. Epub 2017 Dec 18. PMID: 29255002
  • Megat S, Ray PR, Moy JK, Lou TF, Barragán-Iglesias P, Li Y, Pradhan G, Wanghzou A, Ahmad A, Burton MD, North RY, Dougherty PM, Khoutorsky A, Sonenberg N, Webster KR, Dussor G, Campbell ZT, Price TJ. Nociceptor Translational Profiling Reveals the Ragulator-Rag GTPase Complex as a Critical Generator of Neuropathic Pain. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2019 Jan 16;39(3):393-411. Epub 2018 Nov 20. PMID: 30459229
  • Vedantam A, Hou P, Chi TL, Dougherty PM, Hess KR, Viswanathan A. Use of Spinal Cord Diffusion Tensor Imaging to Quantify Neural Ablation and Evaluate Outcome after Percutaneous Cordotomy for Intractable Cancer Pain. Stereotactic and functional neurosurgery. 2017;95(1):34-39. Epub 2017 Jan 14. PMID: 28088799
  • Illias AM, Gist AC, Zhang H, Kosturakis AK, Dougherty PM. Chemokine CCL2 and its receptor CCR2 in the dorsal root ganglion contribute to oxaliplatin-induced mechanical hypersensitivity. Pain. 2018 Jul;159(7):1308-1316. PMID: 29554018
  • Li Y, Tatsui CE, Rhines LD, North RY, Harrison DS, Cassidy RM, Johansson CA, Kosturakis AK, Edwards DD, Zhang H, Dougherty PM. Dorsal root ganglion neurons become hyperexcitable and increase expression of voltage-gated T-type calcium channels (Cav3.2) in paclitaxel-induced peripheral neuropathy. Pain. 2017 Mar;158(3):417-429. PMID: 27902567
  • Dougherty PM. Is Chemotherapy-induced Peripheral Neuropathy More Than Just a Peripheral Nervous System Disorder? Anesthesiology. 2016 May;124(5):992-3. PMID: 26978409
  • Kim HK, Wang Q, Hwang SH, Dougherty PM, Wang J, Abdi S. Bardoxolone Methyl Ameliorates Chemotherapy-Induced Neuropathic Pain by Activation of Phosphorylated Nuclear Factor Erythroid 2-Related Factor 2 in the Dorsal Root Ganglia. Anesthesia and analgesia. 2024 Mar 1;138(3):664-675. Epub 2023 Dec 18. PMID: 38112490
  • North RY, Li Y, Ray P, Rhines LD, Tatsui CE, Rao G, Johansson CA, Zhang H, Kim YH, Zhang B, Dussor G, Kim TH, Price TJ, Dougherty PM. Electrophysiological and transcriptomic correlates of neuropathic pain in human dorsal root ganglion neurons. Brain : a journal of neurology. 2019 May 1;142(5):1215-1226. PMID: 30887021
  • Singhmar P, Huo X, Li Y, Dougherty PM, Mei F, Cheng X, Heijnen CJ, Kavelaars A. Orally active Epac inhibitor reverses mechanical allodynia and loss of intraepidermal nerve fibers in a mouse model of chemotherapy-induced peripheral neuropathy. Pain. 2018 May;159(5):884-893. PMID: 29369966
  • Li Y, Marri T, North RY, Rhodes HR, Uhelski ML, Tatsui CE, Rhines LD, Rao G, Corrales G, Abercrombie TJ, Johansson CA, Dougherty PM. Chemotherapy-induced peripheral neuropathy in a dish: dorsal root ganglion cells treated in vitro with paclitaxel show biochemical and physiological responses parallel to that seen in vivo. Pain. 2021 Jan;162(1):84-96. PMID: 32694383
  • Pachman DR, Qin R, Seisler D, Smith EM, Kaggal S, Novotny P, Ruddy KJ, Lafky JM, Ta LE, Beutler AS, Wagner-Johnston ND, Staff NP, Grothey A, Dougherty PM, Cavaletti G, Loprinzi CL. Comparison of oxaliplatin and paclitaxel-induced neuropathy (Alliance A151505). Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2016 Dec;24(12):5059-5068. Epub 2016 Aug 18. PMID: 27534963
  • Zhang D, Zhou W, Lam TT, Weng C, Bronk L, Ma D, Wang Q, Duman JG, Dougherty PM, Grosshans DR. Radiation induces age-dependent deficits in cortical synaptic plasticity. Neuro-oncology. 2018 Aug 2;20(9):1207-1214. PMID: 29660023
  • Zhang H, Li Y, Yang Q, Liu XG, Dougherty PM. Morphological and Physiological Plasticity of Spinal Lamina II GABA Neurons Is Induced by Sciatic Nerve Chronic Constriction Injury in Mice. Frontiers in cellular neuroscience. 2018 May 24;12:143. doi: 10.3389/fncel.2018.00143. eCollection 2018. PMID: 29881336
  • Viswanathan A, Vedantam A, Hess KR, Ochoa J, Dougherty PM, Reddy AS, Koyyalagunta D, Reddy S, Bruera E. Minimally Invasive Cordotomy for Refractory Cancer Pain: A Randomized Controlled Trial. The oncologist. 2019 Jul;24(7):e590-e596. Epub 2019 Feb 22. PMID: 30796153
  • Kim JH, Dougherty PM, Abdi S. Basic science and clinical management of painful and non-painful chemotherapy-related neuropathy. Gynecologic oncology. 2015 Mar;136(3):453-9. Epub 2015 Jan 10. PMID: 25584767