Vitamin D for Muscle Metabolic Function in Cancer Cachexia

Vitamin D repletion is linked to improved muscle mitochondrial function, lipid deposition and
preservation; however, while vitamin D insufficiency is common in cancer, the mechanistic
effects of vitamin D on muscle metabolic health in cancer patients have not been studied.
This is important to address because cancer cachexia is characterized by marked muscle
wasting, anabolic resistance, ectopic fat infiltration, mitochondrial dysfunction and
contributes to decreased survival. With novel strategies to address this knowledge gap, the
investigators will use a combination of advanced metabolic analytical approaches with
complementary model systems in cell culture and human subjects to understand the biochemical
and physiological mechanisms underlying cancer cachexia in relation to the role of vitamin D
in conjunction with resistance exercise (RE). By combining analyses of muscle size and local
tissue hemodynamics in vivo, metabolomics analyses of muscle tissue and isolated
mitochondria, and changes in anabolic cell signaling, lipid metabolism and oxidative capacity
of primary muscle cells in vitro, the investigators will identify mechanisms underlying
muscle response to vitamin D repletion. Our previous findings, together with data that
exercise improves muscle vitamin D storage and retrieval, suggest that vitamin D repletion
synergizes with RE to improve muscle metabolic function and protein synthesis. Our overall
objective is to examine mitochondrial function and anabolic resistance as potential targets
of action of vitamin D on muscle metabolism, size and strength in preventing the progression
of cachexia. The aims of this study are to: 1) non-invasively quantify lipid redistribution,
local muscle tissue metabolism and muscle mass and strength of cancer patients before and
after 12 weeks of double blinded vitamin D repletion with exercise and protein
supplementation (VitD) compared to exercise and protein supplementation only (Ctl); 2)
determine differences in muscle mitochondrial function in live tissue biopsied from human
gastrocnemius from VitD compared to Ctl; and 3) identify mechanisms whereby vitamin D and
exercise regulate muscle anabolic signaling and mitochondrial activity in primary human
myotube cultures. Our central hypothesis is that vitamin D promotes muscle lipid availability
for β-oxidation in response to exercise, thereby preventing lipotoxicity in the muscle and
potentially improving anabolic sensitivity in muscle during cancer cachexia. The impact of
this project, the first nutrition and exercise study designed as an inexpensive intervention,
is to understand the effect of vitamin D on the metabolic and anabolic dynamics which
underpin dysfunction in cachectic muscle. If vitamin D promotes lipid partitioning, muscle
metabolic function and/or anabolic sensitivity, these adaptations will ultimately improve
cancer therapy by combating cancer cachexia. Further, diffuse optical spectroscopy techniques
have the potential to identify the minimum effective intervention dose for optimizing
metabolic health leading to more practical and individualized lifestyle prescriptions to
reduce health care costs.

Inclusion Criteria:

Patients must have histologically or cytologically confirmed stage II-IV lung cancer and be
planned for definitive non-surgical therapy.

Patients may have a history of prior malignancy.

Mild cancer cachexia, defined by the miniCASCO score of 0-25 points

Vitamin D insufficiency, defined as 25(OH)D < 32 ng/ml

Aged 45 to 75 years. Stratified randomization by age

ECOG performance status ≤ 2 (see Appendix A).

Life expectancy of greater than 3 months

Patients must have normal renal and liver function as defined below:

AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal creatinine within normal
institutional limits OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with
creatinine levels above institutional normal.

Able to swallow thin liquids

No uncontrolled illness including, but not limited to, any of the following:

- Ongoing or active serious infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Uncontrolled cardiac arrhythmia

- Uncontrolled hypertension

- Psychiatric illness or social situation that would preclude compliance with study
requirements

Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas
or mitomycin C) prior to entering the study or those who have not recovered from adverse
events due to agents administered more than 4 weeks earlier.

Patients with untreated brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.
Patients with treated brain metastasis are eligible for this trial, providing they have
completed treatment at least one day prior to registration.

History of allergic reactions to whey or milk proteins.

Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with study
requirements.

Patients with a history of calcium oxalate nephrolithiasis are excluded.

Patients with a significant history of malabsorption (e.g. celiac sprue, short bowel
syndrome, IBD or other, as determined by the treating physician) are excluded.

Patients will not be eligible if actively receiving treatment for vitamin D deficiency and
have had recent (3 month) history of vitamin D supplementation (>1000 IU) or calcium
supplementation (>800mg).

The following exclusion criteria will avoid the possibility of preexisting muscle
impairment: history of congenital myopathies; neurologic disorder involving sequelae of
spinal derangement; disk disease or vascular disease; tremor and rigidity.

Patients will also be excluded if they report lower extremity (LE) surgery or injury to the
LE in the past 3 months or a past medical history of primary hyperparathyroidism; or
rhabdomyolysis.

Additional exclusion criteria include participation in a scheduled resistance exercise
program 1 month;

- metal implants or other contraindications for the MRI;

- diabetes,

- advanced renal disease,

- uncontrolled hypertension;

- a vitamin D status (25(OH)D) of > 32ng/mL.