Principal Investigator

Peter M
Grace
Awardee Organization

University Of Tx Md Anderson Can Ctr
United States

Fiscal Year
2023
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

PQ12 Targeting HDAC6 for Chemotherapy-Induced Neuropathy and Chemobrain

Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairment (CICI) are major side effects of cancer treatment that frequently persist long into survivorship. No drugs have been approved by the US Food and Drug Administration to prevent and/or adequately manage CIPN and CICI. This application aims at filling this void. A concern when designing drugs to manage CIPN and CICI is that they should not impair tumor control. Ideally, agents to control these neurotoxicities should also enhance tumor control. Recent findings indicate that inhibitors of histone deacetylase 6 (HDAC6) meet these goals. HDAC6 de-acetylates non-histone cytosolic proteins like tubulin without inducing epigenetic changes. Recent preclinical and clinical data show promise for HDAC6 inhibitors to improve tumor control. We recently showed that HDAC6 inhibition fully reverses established CIPN in cisplatin-treated mice. This was associated with restoration of mitochondrial health in sensory neurons. Preliminary data indicate that coadministration of HDAC6 inhibitors protect against CIPN by preventing mitochondrial damage. Additional preliminary data indicate that HDAC6 inhibition also reverses established CICI and associated brain mitochondrial damage. Our hypothesis is that HDAC6 inhibition prevents and reverses CIPN and CICI in mice with or without tumors by targeting mitochondrial health, oxidative stress, and downstream neuroimmune pathways. We will test our hypothesis in 3 specific aims: Aim1: Determine the capacity of HDAC6 inhibitors to prevent CIPN in mice with or without tumors. Aim 2: Determine the effect of HDAC6 inhibition on established CIPN. Aim 3: Determine whether the beneficial effects of HDAC6 inhibition extend to CICI. In aims 1 and 3, we will investigate the effect of HDAC6 inhibitors on tumor control and ensure that HDAC6 inhibitors also prevent CIPN and CICI in the presence of a tumor. This study is innovative because we propose to target HDAC6 activity in neurons to control neurotoxicities while at the same time enhancing cancer control. The expected outcome is significant because it will identify HDAC6 inhibition as a realistic novel approach to control CIPN and CICI. This will increase the quality of life of millions of cancer patients and survivors. Clinical trials to examine the effect of HDAC6 inhibitors on tumor control are already underway, and therefore the expected results of this project should rapidly convince clinicians to examine the value of HDAC6 inhibitors for management of both CIPN and CICI. Identification of HDAC6 inhibitors as drugs that can be used after completion of chemotherapy to completely resolve established CIPN and CICI will be of great benefit for cancer survivors suffering every day from these persistent neurotoxicities.

Publications

  • Huo X, Reyes TM, Heijnen CJ, Kavelaars A. Cisplatin treatment induces attention deficits and impairs synaptic integrity in the prefrontal cortex in mice. Scientific reports. 2018 Nov 27;8(1):17400. PMID: 30479361
  • Kavelaars A, Heijnen CJ. T Cells as Guardians of Pain Resolution. Trends in molecular medicine. 2021 Apr;27(4):302-313. Epub 2021 Jan 8. PMID: 33431239
  • Laumet G, Edralin JD, Dantzer R, Heijnen CJ, Kavelaars A. Cisplatin educates CD8+ T cells to prevent and resolve chemotherapy-induced peripheral neuropathy in mice. Pain. 2019 Jun;160(6):1459-1468. PMID: 30720585
  • Li J, Ma J, Lacagnina MJ, Lorca S, Odem MA, Walters ET, Kavelaars A, Grace PM. Oral Dimethyl Fumarate Reduces Peripheral Neuropathic Pain in Rodents via NFE2L2 Antioxidant Signaling. Anesthesiology. 2020 Feb;132(2):343-356. PMID: 31939850
  • McAlpin BR, Mahalingam R, Singh AK, Dharmaraj S, Chrisikos TT, Boukelmoune N, Kavelaars A, Heijnen CJ. HDAC6 inhibition reverses long-term doxorubicin-induced cognitive dysfunction by restoring microglia homeostasis and synaptic integrity. Theranostics. 2022 Jan 1;12(2):603-619. doi: 10.7150/thno.67410. eCollection 2022. PMID: 34976203
  • Zhang J, Ma J, Trinh RT, Heijnen CJ, Kavelaars A. An HDAC6 inhibitor reverses chemotherapy-induced mechanical hypersensitivity via an IL-10 and macrophage dependent pathway. Brain, behavior, and immunity. 2022 Feb;100:287-296. Epub 2021 Dec 13. PMID: 34915156
  • Boukelmoune N, Laumet G, Tang Y, Ma J, Mahant I, Singh SK, Nijboer C, Benders M, Kavelaars A, Heijnen CJ. Nasal administration of mesenchymal stem cells reverses chemotherapy-induced peripheral neuropathy in mice. Brain, behavior, and immunity. 2021 Mar;93:43-54. Epub 2020 Dec 11. PMID: 33316379
  • Laumet G, Ma J, Robison AJ, Kumari S, Heijnen CJ, Kavelaars A. T Cells as an Emerging Target for Chronic Pain Therapy. Frontiers in molecular neuroscience. 2019 Sep 11;12:216. doi: 10.3389/fnmol.2019.00216. eCollection 2019. PMID: 31572125
  • Zhang J, Junigan JM, Trinh R, Kavelaars A, Heijnen CJ, Grace PM. HDAC6 Inhibition Reverses Cisplatin-Induced Mechanical Hypersensitivity via Tonic Delta Opioid Receptor Signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2022 Oct 19;42(42):7862-7874. Epub 2022 Sep 12. PMID: 36096670
  • English K, Shepherd A, Uzor NE, Trinh R, Kavelaars A, Heijnen CJ. Astrocytes rescue neuronal health after cisplatin treatment through mitochondrial transfer. Acta neuropathologica communications. 2020 Mar 20;8(1):36. PMID: 32197663
  • Ma J, Huo X, Jarpe MB, Kavelaars A, Heijnen CJ. Pharmacological inhibition of HDAC6 reverses cognitive impairment and tau pathology as a result of cisplatin treatment. Acta neuropathologica communications. 2018 Oct 1;6(1):103. PMID: 30270813
  • Ma J, Trinh RT, Mahant ID, Peng B, Matthias P, Heijnen CJ, Kavelaars A. Cell-specific role of histone deacetylase 6 in chemotherapy-induced mechanical allodynia and loss of intraepidermal nerve fibers. Pain. 2019 Dec;160(12):2877-2890. PMID: 31356453
  • Laumet G, Bavencoffe A, Edralin JD, Huo XJ, Walters ET, Dantzer R, Heijnen CJ, Kavelaars A. Interleukin-10 resolves pain hypersensitivity induced by cisplatin by reversing sensory neuron hyperexcitability. Pain. 2020 Oct;161(10):2344-2352. PMID: 32427749
  • Chiang ACA, Huo X, Kavelaars A, Heijnen CJ. Chemotherapy accelerates age-related development of tauopathy and results in loss of synaptic integrity and cognitive impairment. Brain, behavior, and immunity. 2019 Jul;79:319-325. Epub 2019 Apr 3. PMID: 30953771
  • Ma J, Goodwani S, Acton PJ, Buggia-Prevot V, Kesler SR, Jamal I, Mahant ID, Liu Z, Mseeh F, Roth BL, Chakraborty C, Peng B, Wu Q, Jiang Y, Le K, Soth MJ, Jones P, Kavelaars A, Ray WJ, Heijnen CJ. Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments. Pain. 2021 Oct 1;162(10):2599-2612. PMID: 33872235
  • Alexander JF, Mahalingam R, Seua AV, Wu S, Arroyo LD, Hörbelt T, Schedlowski M, Blanco E, Kavelaars A, Heijnen CJ. Targeting the Meningeal Compartment to Resolve Chemobrain and Neuropathy via Nasal Delivery of Functionalized Mitochondria. Advanced healthcare materials. 2022 Apr;11(8):e2102153. Epub 2022 Jan 27. PMID: 35007407
  • Kavelaars A, Heijnen CJ. Immune regulation of pain: Friend and foe. Science translational medicine. 2021 Nov 10;13(619):eabj7152. Epub 2021 Nov 10. PMID: 34757809
  • Boukelmoune N, Chiu GS, Kavelaars A, Heijnen CJ. Mitochondrial transfer from mesenchymal stem cells to neural stem cells protects against the neurotoxic effects of cisplatin. Acta neuropathologica communications. 2018 Dec 12;6(1):139. PMID: 30541620
  • Alexander JF, Seua AV, Arroyo LD, Ray PR, Wangzhou A, Heiβ-Lückemann L, Schedlowski M, Price TJ, Kavelaars A, Heijnen CJ. Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics. 2021 Jan 1;11(7):3109-3130. doi: 10.7150/thno.53474. eCollection 2021. PMID: 33537077
  • Laumet G, Edralin JD, Dantzer R, Heijnen CJ, Kavelaars A. CD3+ T cells are critical for the resolution of comorbid inflammatory pain and depression-like behavior. Neurobiology of pain (Cambridge, Mass.). 2020 Jan 21;7:100043. doi: 10.1016/j.ynpai.2020.100043. eCollection 2020 Jan-Jul. PMID: 32510006
  • Singh SK, Krukowski K, Laumet GO, Weis D, Alexander JF, Heijnen CJ, Kavelaars A. CD8+ T cell-derived IL-13 increases macrophage IL-10 to resolve neuropathic pain. JCI insight. 2022 Mar 8;7. (5). PMID: 35260535
  • Chiang ACA, Seua AV, Singhmar P, Arroyo LD, Mahalingam R, Hu J, Kavelaars A, Heijnen CJ. Bexarotene normalizes chemotherapy-induced myelin decompaction and reverses cognitive and sensorimotor deficits in mice. Acta neuropathologica communications. 2020 Nov 12;8(1):193. PMID: 33183353
  • Mustafa S, Bajic JE, Barry B, Evans S, Siemens KR, Hutchinson MR, Grace PM. One immune system plays many parts: The dynamic role of the immune system in chronic pain and opioid pharmacology. Neuropharmacology. 2023 May 1;228:109459. Epub 2023 Feb 11. PMID: 36775098
  • Singh AK, Mahalingam R, Squillace S, Jacobson KA, Tosh DK, Dharmaraj S, Farr SA, Kavelaars A, Salvemini D, Heijnen CJ. Targeting the A3 adenosine receptor to prevent and reverse chemotherapy-induced neurotoxicities in mice. Acta neuropathologica communications. 2022 Jan 29;10(1):11. PMID: 35093182