Patients with cancer have multiple symptoms, such as pain, fatigue, sleep disturbance, and poor appetite that cause significant distress, impair function and rehabilitation, and may cause treatment delays or premature treatment termination. These symptoms are caused by both the cancer and its therapy. When the cancer is incurable, as is multiple myeloma (MM), the balance between the side effects of aggressive treatment and optimal function becomes critical. There is growing evidence that some of these symptoms may cluster together and share common physiologic mechanisms, creating a "symptom burden" that is the subjective counterpart of tumor burden. The recent evolution of the animal "sickness behavior" model which is strikingly similar to symptoms reported by cancer patients undergoing treatment (Cleeland et al., 2003;Lee et al., 2004, Dantzer &Kelley, 2007), presents an exciting opportunity I) to test for possible physiologic mechanisms of symptom production, and 2) to examine new strategies to reduce or prevent cancer-related symptoms. The overall hypothesis to be tested in this program project is that increases in specific proinflammatory cytokines, especially IL-I, IL-6 and TNF-a, and activation of their precursor, NF-kb, are associated with the emergence of individual symptoms or clusters of treatment-related symptoms, and that modulation of these inflammatory pathways will reduce both the prevalence and severity of symptoms. Preliminary data presented for this program are supportive of this hypothesis. A project of this nature necessitates a broadly based integrated and multidisciplinary Program Project that includes expertise in longitudinal symptom assessment, immunology, quantative motor and sensory assessment, and animal models of symptoms and disease where mechanisms of symptom expression can be examined. A special requirement is for the development of statistical models that can account for the relationship of symptom and biological variables over time. Components of the individual projects will follow MM patients from diagnosis through induction therapy, transplantation, and maintenance therapy. MM presents an ideal disease to test these hypotheses, since proinflammatory cytokines play a major role in the development of the disease, aggressive treatments exacerbate production of proinflammatory cytokines and, in recent years, there has been an increase in knowledge about and availability of agents for inflammatory blockade that make mechanistic symptom control a real possibility in the trajectory of this disease. Our long-term objective is to create a foundation for a mechanism-driven symptom control strategy for managing disease and treatment-related symptoms. Having the ability to reduce symptom burden or even prevent these consequences from therapy would be of potential benefit to thousands of cancer patients and survivors by improving the tolerability of treatment and reducing posttreatment residual symptoms.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA124787-05
Application #
8331191
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Program Officer
O'Mara, Ann M
Project Start
2008-09-18
Project End
2014-08-31
Budget Start
2012-09-05
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$2,113,288
Indirect Cost
$713,106
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Colvin, L A; Dougherty, P M (2015) Peripheral neuropathic pain: signs, symptoms, mechanisms, and causes: are they linked? Br J Anaesth 114:361-3
Robinson, C R; Dougherty, P M (2015) Spinal astrocyte gap junction and glutamate transporter expression contributes to a rat model of bortezomib-induced peripheral neuropathy. Neuroscience 285:10-Jan
Shi, Qiuling; Wang, Xin Shelley; Li, Guojun et al. (2015) Racial/ethnic disparities in inflammatory gene single-nucleotide polymorphisms as predictors of a high risk for symptom burden in patients with multiple myeloma 1 year after diagnosis. Cancer 121:1138-46
Wang, Xin Shelley; Shi, Qiuling; Williams, Loretta A et al. (2015) Longitudinal analysis of patient-reported symptoms post-autologous stem cell transplant and their relationship to inflammation in patients with multiple myeloma. Leuk Lymphoma 56:1335-41
de Carvalho Barbosa, Mariana; Kosturakis, Alyssa K; Eng, Cathy et al. (2014) A quantitative sensory analysis of peripheral neuropathy in colorectal cancer and its exacerbation by oxaliplatin chemotherapy. Cancer Res 74:5955-62
Mao-Ying, Qi-Liang; Kavelaars, Annemieke; Krukowski, Karen et al. (2014) The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model. PLoS One 9:e100701
Zhang, Haijun; Dougherty, Patrick M (2014) Enhanced excitability of primary sensory neurons and altered gene expression of neuronal ion channels in dorsal root ganglion in paclitaxel-induced peripheral neuropathy. Anesthesiology 120:1463-75
Robinson, C R; Zhang, H; Dougherty, P M (2014) Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy in the rat. Neuroscience 274:308-17
Walker, Adam K; Hsieh, Jennifer; Luu, Katherine V et al. (2014) Activation of lung toll-like receptors does not exacerbate sickness responses to lipopolysaccharide in mice. Brain Behav Immun 38:211-9
Li, Yan; Zhang, Haijun; Zhang, Hongmei et al. (2014) Toll-like receptor 4 signaling contributes to Paclitaxel-induced peripheral neuropathy. J Pain 15:712-25

Showing the most recent 10 out of 115 publications