With stagnant cure rates, there is a severe unmet need for strategies to improve oral and all other types of aerodigestive cancer survival. There are no robust chemoprevention drugs or other treatments for high risk oral precancerous conditions or field carcinogenesis despite 40 years of clinical trial research. High risk oral precancerous conditions (such as leukoplakia) represent a standard target for chemoprevention interventions. Type II anti-diabetic agents, including pioglitazone and metformin, are promising cancer prevention drugs for oral cavity preneoplasia that we have used in NCI sponsored clinical trials. They have adequate safety and moderate efficacy in human trials, however, individually are likely not sufficient to advance to large scale clinical trials. These agents have differing mechanisms of action which each attack different events in oral carcinogenesis. In this project, we propose to conduct a phase IIa 12 week clinical trial with combination BID pioglitazone-metformin (15mg-500mg) in oral preneoplasia patients. We have assembled a consortium of clinics in Minneapolis/St. Paul MN for efficient accrual to this trial. We will examine pharmacodynamic endpoints in specimens based on both the mechanisms of the agents and how they may affect T cell subsets before and after treatment. Further, we will also analyze leukoplakia specimens and adjacent normal mucosa specimens by RNA-Seq before and after treatment, which will shed light on effects of the drugs as well as any putative “off target” effects. At the completion of this project, we will have a better understanding of pioglitazone and metformin effects on oral carcinogenesis, as well as, an early stage clinical trial which could be expanded to larger randomized trials with a promising cancer prevention strategy for oral preneoplasia or other tobacco-associated malignancies.

Multiple Myeloma (MM) patients undergoing Autologous Stem Cell Transplantation (ASCT) experience clinically significant negative sequelae affecting disease prognosis, survival, and quality of life. These sequelae include increase in production of pro-inflammatory cytokines, higher occurrences of neutropenic fever and higher symptom burden (e.g., depression, pain) which are associated with circadian rhythm disruption (CRD). CRD involves disruption in naturally occurring 24-hour cycles of hormone secretion, temperature and activity. CRD raises production of pro-inflammatory cytokines unfolding a cascade of negative effects that include higher symptom burden and risk of developing neutropenic fever. CRD has been associated with poorer prognosis and survival. Our recently completed R21 study showed that morning circadian-effective illumination of patients' hospital rooms resulted in significantly higher nocturnal melatonin levels, reduced depression and production of inflammatory cytokines compared to the circadian-ineffective group (control). In the active group, an improvement in sleep and reduction in neutropenic fever was observed. Our R21 results also showed a strong negative relationship between melatonin levels and pro-inflammatory cytokines. Therefore, for the proposed multi-site randomized controlled trial (RCT) we hypothesize that circadian entrainment resulting from morning light exposure will lead to better sleep, lower levels of proinflammatory cytokines and symptom burden, as well as fewer occurrences of neutropenic fever. We will investigate if circadian-effective illumination, of patients' hospital rooms/outpatient settings during ASCT, promotes circadian entrainment and improves sleep, and if circadian entrainment reduces inflammation. We will also investigate whether better entrainment and lower levels of pro-inflammatory markers are associated with fewer occurrences of neutropenic fever and reduced symptom burden. The circadian stimulating light will be installed in the outpatient setting/hospital rooms since transplants are performed in both settings. A unique advantage of our intervention is that it does not require any patient effort because the circadianactive light is delivered throughout the entire room. The project will determine if: 1) circadian-effective light compared to circadian-ineffective light, delivered during ASCT results in circadian rhythm entrainment; 2) circadian entrainment reduces pro-inflammation cytokines and mediates the effects of circadian-effective light on the cytokines; and 3) reduced levels of inflammatory cytokines are associated with reduced occurrence of neutropenic fever and lower symptom burden in patients.

Improving the management of acute pain, psychological distress, and other surgical outcomes among women undergoing surgery for suspected gynecologic malignancies would proactively reach a population vulnerable to developing chronic pain. Non-pharmacological interventions that address multiple biobehavioral dimensions of pain (e.g., cognitive, behavioral) may be most effective at preventing the transition to chronic pain. Yoga (meditation, movements, and breathing) is a mind-body intervention that reduces pain, psychological distress, and sleep disturbances, and improves physical function. Yoga has a potential advantage over other perioperative non-pharmacological interventions because of additional components that also support multiple goals of postoperative usual care (e.g., early postoperative mobilization, encouraging deep breathing) and could help improve other surgical management outcomes (e.g., functional recovery, length of stay). Thus, yoga may optimally improve pain, psychological distress and other surgical management outcomes through multiple biobehavioral mechanisms. Yet, limited rigorous research has evaluated yoga delivered in coordination with surgical care. The proposed eHealth Mindful Movement and Breathing (eMMB) is innovative because it adapts the core components of yoga with the intention to remove key barriers to participation and mitigate the transition from acute to chronic pain. We propose to conduct a randomized controlled trial of eMMB compared to an empathic attention control (AC) among 122 women undergoing surgery for suspected gynecologic malignancies. We aim to determine the efficacy of eMMB for improving pain and other surgical outcomes (Aim 1), and to examine the effect of eMMB on proposed proximal biobehavioral outcomes (Aim 2). We will also conduct semi-structured interviews with key stakeholders (n=18-24; patients, champions, providers, yoga instructors) to assess factors that serve as barriers or facilitators to sustainably implementing eMMB in clinical care (Aim 3). Understanding these factors will inform implementation strategies to be tested in a future study. In summary, eMMB reaches patients during the perioperative period and has the potential to prevent the transition from acute to chronic pain with a low-cost intervention. The brevity and accessibility of the intervention, and the increasing popularity of yoga, make eMMB a strong candidate for future implementation. Results from this study in women undergoing surgery for gynecologic malignancies may be generalizable to other surgical procedures and thus have important public health implications for reducing the growing population affected by chronic pain. The proposed research is aligned with the scientific opportunity for mitigating long-term effects of cancer treatment highlighted by the National Cancer Institute.

The slow growing nature of most prostate cancers (PCa) provides multiple windows of opportunity to block or delay disease progression to significantly reduce patient suffering and mortality. This is especially true following the failure of radical prostatectomy (RP) and radiation therapy (RT) of PCa prior to androgen deprivation therapy (ADT; i.e., medical or surgical castration). Biochemical recurrent PCa is sensitively indicated by rising blood prostate specific antigen (PSA). ADT is not curative and causes many serious adverse effects. Our goal is to develop Angelica gigas Nakai (AGN, Korean Angelica) root ethanolic extract or its constituent(s) as a safer and practical modality for PCa interception akin to secondary prevention to delay ADT or avoid it entirely. We hypothesize that (1) the PCa interception efficacy of AGN and its pyranocoumarins in animal models is extendable into human PCa patients, given sufficient AGN dosage and exposure duration; (2) multiple mechanisms including immune surveillance and suppression of inflammation contribute to the clinical cancer interception activity. The scientific premise is based on the presence of novel active pyranocoumarin compounds distinct from those in soy, tea, fish oil, raspberries, mushrooms, and cannabis and reported broad spectrum anticancer efficacy in animal cancer models. Moreover, we have demonstrated a) Oral bioavailability and favorable pharmacokinetic (PK) metrics in rodents and in humans; b) Cytochrome P450 (CYP) 2C19 and 3A4 first-pass conversion of pyranocoumarins decursin (D) and decursinol angelate (DA) to their metabolite decursinol (DOH); c) Proficient tissue retention of decursinol in mouse target prostate; d) Animal modeling of AGN and decursinol showing independence of the androgen receptor axis, avoiding side effects of ADT drugs and making blood PSA a reliable readout for cancer burden; e) AGN enhanced immune and decreased inflammatory gene signatures in an animal PCa model; and f) A single AGN dose in human subjects increased natural killer [NK] mRNA signature and decreased IL-8 chemokine mRNA in their peripheral blood mononuclear cells. We propose 3 specific aims in post-RP and post-RT patients with rising plasma PSA that is “clean” (due to prostate already removed) and indicative of the biochemical recurrent PCa burden. Aim 1. Characterize pyranocoumarin PK dose response proportionality to AGN supplement and food effects in 12 patients to probe any metabolic ceiling and minimize food-herbal interaction. Aim 2. Evaluate safety and recurrent PCa (PSA)-interception efficacy of twice daily AGN supplement in a Phase I/II trial with 36 patients. Aim 3. Measure acute- and repeated-dose PK metrics, CYP 2C19 and 3A4 metabolizer status and changes of immune and inflammation biomarkers to correlate to PSA outcomes. Impacts: The safety information and a favorable PSA response will guide future randomized control trials to prevent or treat PCa and other cancers. The novel knowledge on PK dose response, repeated dose PK behavior, CYP pharmacogenetics and the immune biomarkers not only fills in critical gaps for AGN supplements in cancer patients, but also is exportable to disease prevention and therapy beyond oncology.