Grant summaries

 

 

Breast Cancer Muscle Mass Study

Chemotherapy drugs are commonly dosed according to patients’ body surface area, which is calculated from their weight and height. Normalizing drug doses to body surface area does not account for the wide variability in the proportions of fat and skeletal muscle in patients of the same body size. Neglecting to account for differences in body composition has critical implications for the dosing of chemotherapeutic drugs that are distributed and metabolized in the lean (muscle) compartment. Conventional dosing of water-soluble chemotherapy drugs according to body surface area overestimates the volume of drug distribution in cancer patients with low muscle mass, resulting in higher drug concentrations in these patients. This “overdosing” of chemotherapy can lead to severe, dose-limiting treatment toxicities. This problem is especially severe in cancer patients who experience muscle wasting (cachexia) due to their cancer.

In breast cancer patients, fatigue, neuropathy, and cognitive impairment are three of the most common and distressing side effects of cytotoxic chemotherapy. For many breast cancer survivors, these chemotherapy-induced toxicities persist long after treatment has ceased. There is a critical need to identify biomarkers that predict which breast cancer patients are at greatest risk for experiencing chemotherapy-related toxicities. Neglecting to account for variability in body composition has hampered efforts to optimize and individualize chemotherapy regimens in breast cancer patients.

The objectives of this proposal are to demonstrate the variability in chemotherapy drug dosing relative to muscle mass in breast cancer patients, and then evaluate whether the prevalence, severity, and durability of fatigue, neuropathy, and cognitive dysfunction are related to this variability in chemotherapy dosing. We will retrospectively and prospectively evaluate breast cancer patients that were conventionally dosed with chemotherapy according to body surface area. We will re-calculate each patient’s chemotherapy doses normalized to lean body mass. We hypothesize that breast cancer patients that received high drug doses per kilogram lean body mass are more susceptible to long-lasting fatigue, neuropathy, and cognitive impairment than patients that received low drug doses per kilogram lean body mass.

In Aim 1, we will conduct a retrospective chart review of breast cancer survivors that received cytotoxic chemotherapy while being treated for cancer. We will examine whether patients that received high doses of chemotherapy (normalized to lean body mass) experience persistent fatigue and neuropathy more frequently than patients that received low doses of chemotherapy (normalized to lean body mass). In Aim 2, we will prospectively determine whether re-calculating chemotherapy doses normalized to lean body mass predicts which patients exhibit reduced physical activity and cognitive deficits, both during active chemotherapy treatment and survivorship. We will measure body composition in recently diagnosed breast cancer patients prior to their first cycle of chemotherapy and then will monitor their daily activity patterns during and after chemotherapy. We will also assess cognitive function by administering a battery of cognitive tests after the patients commence chemotherapy.

Factoring each patient’s unique body composition features into their treatment planning process will transform clinical practice and bring us closer to the realization of personalized chemotherapy. Minimizing toxicities will increase patients’ adherence to chemotherapy, improve patient outcomes, and extend survival. Reducing the risk of persistent fatigue, neuropathy, and cognitive impairment will improve physical and mental function, reduce social isolation, and dramatically enhance quality of life in breast cancer survivors.


Pancreatic Cancer Extracellular Vesicles and TLR7 Signaling

This proposal combines fundamental discoveries made by our group with new preliminary data to generate a novel and compelling direction for our research. Previously, we elucidated critical neuronal signaling pathways within the MBH for the establishment of acute sickness responses and chronic disease-associated cachexia, and demonstrated the unique signaling cascades that distinguish central inflammation from that found in the periphery.

However, clinical trials aimed at blocking individual inflammatory pathways in cachexia were all unsuccessful, supporting the idea that critical signaling pathways remain undiscovered in this condition. We now take advantage of a novel murine model of PDAC cachexia to explore a unique mechanism for the induction and maintenance of this debilitating metabolic syndrome. Specifically, our new data demonstrate that PDAC tumors elaborate extracellular vesicles (EVs) containing endogenous microRNA (miR) ligands of toll-like receptors (TLRs). These EVs are capable of driving microglial inflammatory responses via TLR7 in vitro, and reproduce the entire cachexia syndrome when delivered in vivo. However, there are currently no data demonstrating that circulating tumor-derived EVs act within the brain to produce cachexia, nor any data demonstrating a role for TLR7 in this process. We hypothesize that PDAC tumor-derived EVs elicit MBH inflammation and cachexia via activation of TLR7 by EV miRNAs.

To test this hypothesis, we will pursue studies that define the cellular and molecular pathways linking systemic exposure to PDAC EVs with cachexia, with a focus on elucidating the role of MBH microglia in receiving and amplifying this signal via the induction of local cytokine production and leukocyte recruitment. The long-term goal of our research is to provide novel therapeutic options to improve survival and quality of life in patients with cancer cachexia.


Recruitment of immune cells into the brain during pancreatic cancer

Illness behaviors, metabolic disturbances, and cognitive decline are common in pancreatic cancer patients, and contribute substantially to quality of life and ultimate survival. Other illness-induced morbidities including lethargy also compromise the ability of patients to recover from life-saving or extending interventions, and diminish the motivational drive to aggressively battle the condition.

Although cachexia in cancer patients was described more than two thousand years ago, the central mechanisms underlying this disorder are poorly understood. Furthermore, there is currently no effective pharmaceutical treatment. Cognitive decline is common in all cancer patients, and frequently occurs prior to initiation of therapy.

Our laboratory is dedicated to unraveling the basic mechanisms whereby cancer triggers neuroinflammation, a key driver of cachexia and cognitive decline in cancer patients. In this proposal, we will focus on understanding the scope and mechanism by which pancreatic cancer induces the recruitment of monocytes and neutrophils into the CNS. The significance of this proposal resides in its unique combination of our historical focus on neuroendocrinology and neuroinflammation, with new collaborations and efforts directed at understanding the extent and mechanisms of neurocognitive decline in cancer patients.

The long-term goal of our research is to gain mechanistic understanding of the acute illness response and how it is transitioned into chronic neuroinflammation in order to develop more effective therapeutic interventions.