Translating academic discoveries into clinical investigation remains a major barrier in translational science, particularly when investigators lack the regulatory infrastructure required to sponsor clinical trials. These challenges are especially pronounced for natural product therapeutics, which often lack commercial sponsorship despite promising preclinical evidence. The Penn State Cancer Institute established an Investigator-Initiated Trial Sponsor Support Unit (SSU) to facilitate investigator-initiated trials and support progression toward National Cancer Institute designation. We describe a translational science case study of a Sponsor-Proxy operational model in which a centralized institutional unit performs sponsor-level regulatory and trial infrastructure functions while investigators retain scientific and clinical leadership. Two National Institutes of Health-funded trials evaluating Angelica gigas Nakai extract (INM176) illustrate this framework. The SSU authored regulatory documentation including Investigator's Brochures, coordinated Investigational New Drug submissions, and supported trial infrastructure while clinical teams maintained participant oversight. Both trials achieved activation timelines of 112 and 105 days, shorter than previously reported activation times and within National Cancer Institute operational benchmarks. Sponsor-level oversight continued throughout trial conduct, including regulatory reporting, safety monitoring, and protocol amendment support. This case study demonstrates how centralized institutional expertise can overcome sponsor-level barriers and enable translation of basic science discoveries into investigator-initiated early-phase clinical trials.

Background Cysteine is a multifunctional amino acid that can be oxidized affecting disulfide bond formation, redox signaling, and protein function. Reactive oxygen species (ROS) and the metabolic environment dictate cysteine uptake and oxidation status-especially in redox sensitive pathways. As many chemotherapeutic agents increase ROS, including the standard care for glioblastoma (GBM), temozolomide (TMZ), we hypothesized that TMZ-resistant (TMZ-R) GBM would have increased ROS affecting cysteine reactivity that could be therapeutically targeted.Methods Here, to study the metabolic state within drug sensitive and resistant GBM, we used metabolite tracing with13 C-Cyst(e)ine, specialized cysteine reactivity proteomics and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) screening with drug treatments to determine the efficacy of targeting cysteine metabolic pathways with our designer selenium drug in both patient-derived cell lines and patient-derived xenograft GBM orthotopic models.Results We show that TMZ-R have increased cyst(e)ine uptake, cysteine reactivity, and sensitivity to selenium (Se)-containing compounds-which can bind cysteine-in vitro and in vivo. We show that in TMZ-R models selenium compound treatment increases the need for thioredoxin reductases where co-treatment of Se compounds and the thioredoxin inhibitor auranofin significantly improves overall survival in mouse models.Conclusions Overall, our findings show a unique metabolic environment in TMZ-R models where designer brain penetrant Se-containing compounds target cysteine reactivity within proteins necessary for cancer cell survival and hold therapeutic potential.

Angelica gigas Nakai (AGN) root is a medicinal herbal widely used in traditional medicine in Korea. AGN root ethanolic extracts have been marketed as dietary supplements in the United States for memory health and pain management. We have recently reviewed the pharmacokinetics (PK) and first-pass hepatic metabolism of ingested AGN supplements in humans for the signature pyranocoumarins decursin (D, Cmax 1x), decursinol angelate (DA, Cmax 10x) and their common botanical precursor and hepatic metabolite decursinol (DOH, Cmax 1000x). Here we update in vivo medicinal activities of AGN and/or its pyranocoumarins and furanocoumarin nodakenin in cancer, pain, memory loss, cerebral ischemia reperfusion stroke, metabolic syndrome and vascular endothelial dysfunctions, anxiety, sleep disorder, epilepsy, inflammatory bowel disease, osteoporosis and osteoarthritis. Given their polypharmacology nature, the pertinent mechanisms of action are likely misrepresented by many cell culture studies that did not consider the drug metabolism knowledge. We report here Rho-associated protein kinases (ROCK1/2) as novel targets for DA and DOH. Combining with published inhibitory activity of DOH on acetylcholinesterase, agonist activity of DOH and antagonist/degrader activity of DA/D on androgen and estrogen receptors, D/DA promoting activity for glutamic acid decarboxylase (GAD)- gamma-aminobutyric acid (GABA) inhibitory axis and inhibition of glutamate dehydrogenase (GDH), monoamine oxidase-A (MAO-A) and transient receptor potential vanilloid 1 (TRPV1), we postulate their contributions to neuro-cognitive, metabolic, oncologic, vascular and other beneficial bioactivities of AGN extracts. A clinical trial is being planned for an AGN extract to manage side effects of androgen deprivation therapy in prostate cancer patients.

Selenium (Se) is an essential trace mineral crucial for human health. Nearly a dozen human clinical trials with seleno-methionine (SeMet) and selenized-yeast (contains mostly SeMet) for the prevention of non-cutaneous solid organ cancers in North America and European countries conclusively refuted their utility. We have articulated two lessons from these trials: (1) the anti-oxidant hypothesis was tested in inappropriate Se-adequate populations, and (2) the selection of these Se forms was not supported by cell culture and animal efficacy data. Nevertheless, preclinical studies of proximal methylselenol precursors ("methyl Se") have shown many desirable attributes, involving crucial molecules and pathways in cancer epithelial cells, vascular endothelial, immune and inflammatory cells in the tumor microenvironment, for potential use as chemopreventive and therapy agents. Methylseleninic acid and Se-methylselenocysteine are prototypical methyl-Se, yet not equal in their targets. Selenate, selenite and selenious acid had been recently studied in human clinical trials, providing novel safety data, but, missing critical genotoxicity assessments. Given the popularity of Se-enriched foods in China and a continued presence of nutritional Se deficiency in many localities, we discuss recommendations for clinical studies of Se forms for cancer therapy or chemoprevention in China and other countries with similar Se nutrition predicament.

Our previous work has shown a synergistic tumoricidal action of the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) and the autophagy inhibitor chloroquine (CQ) on HK2-addicted prostate cancers in animal models through intraperitoneal injections. Here we developed high performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) methods for 2-DG and clinically favored drug hydroxychloroquine (HCQ) and explored PK interaction of the orally administered drugs in a jugular vein cannulated male rat model, which allowed serial blood collection before and 0.5, 1, 2, 4 and 8 h after a single gavage dose of each drug alone or simultaneously after appropriate washout periods between the drugs. The results demonstrated a rapid and satisfactory separation of 2-DG standard from common monosaccharides by HPLC-MS-MS multi-reaction monitoring (MRM) and the presence of endogenous "2-DG". Application of the HPLC-MS-MS 2-DG and HCQ methods to sera samples of 9 evaluable rats showed a peak time (Tmax) of 2-DG of 0.5 h after 2-DG dosing alone or with HCQ and glucose-like PK behavior. With a seemingly bi-modal time course for HCQ, the Tmax for HCQ dosing alone (1.2 h) was faster than that for the combination (2 h; p = 0.013, 2-tailed t-test). After combination dosing, the peak concentration (Cmax) and area under the curve (AUC) of 2-DG were decreased by 54% (p < 0.0001) and 52%, whereas those for HCQ were decreased by 40% (p = 0.026) and 35%, respectively, compared to single dosing. The data suggest significant negative PK interactions between the two oral drugs taken simultaneously and warrant optimization efforts for the combination regimen.

170 Background: The ethanol extract of the root of Angelica gigas Nakai (AGN) dose-dependently inhibits animal models of prostate cancer. Multi-omic analyses have implicated immune and anti-inflammatory responses in the anti-cancer action. In our single dose-PK study (NCT02114957) in healthy volunteers with AGN dietary supplement CognI.Q, we observed a near doubling of the natural killer (NK) mRNA signature in peripheral blood mononuclear cells (PBMC) at 24 h after dosing while the inflammatory cytokine IL-8 mRNA was decreased by one half over the pre-dose baseline. Given NK incapacitation and inflammation have been linked to prostate cancer, the current trial (NCT03630328) was designed to assess safety and to delineate CognI.Q-specific immune and anti-inflammation functions. Methods: We used a double-blinded, placebo-controlled and crossover trial design to monitor hepatic and renal safety metrics based on Comprehensive Metabolic Panel (CMP) and compare the immune cell and cytokine responses to CognI.Q and placebo. Supplement period of 3 weeks was followed with a 2-week washout period. We employed the Ella microfluidic multiplex immunoassay to evaluate select plasma cytokines. Results: Fourteen healthy men completed the trial protocol. Physical examination on study visit days did not reveal any adverse events. Blood CMP monitoring detected abnormal hepatic integrity values in three subjects, all in the second washout period and were attributed to use of anti-allergy medication, an herbal tea for tooth ache, and excessive alcohol, respectively. Analysis of plasma cytokines detected corresponding elevation of MIG, CCL4, CXCL10 and IL-8 with these hepatic damage events. With the exclusion of these subjects or time point, the plasma cytokine measurement did not reveal a significant response to CognI.Q supplement vs. placebo. Conclusions: CognI.Q supplement at the current recommended dose (400 mg, twice per day) did not impair hepatic integrity or renal function, nor did it modulate select plasma cytokines in healthy men. Phase I dose-escalation trials should be implemented to establish safety profile and assess immune and inflammation modulatory effects of AGN supplement beyond the current dose. Clinical trial information: NCT03630328 .

The dried roots of Angelica gigas Nakai (AGN) plants (also known as Korean Angelica or Cham Dang Gui) are a popular medicinal herbal ingredient in Korea. Herbal dietary supplements made of imported AGN root extracts from Korea have been marketed in the United States for cognitive memory health and pain relief. Although AGN plants are sold by plant nurseries in the US for ornamental purposes, their cultivation for potential herbal medicinal use has not been reported in the academic literature. Here we describe the signature chemical profile of AGN plants cultivated in Hershey, and State College, in the State of Pennsylvania (PA) from 2017 to 2023. Stem rot was a disease that led to the premature death of some growing and flowering plants. We analyzed dried roots harvested in 2018 (N = 5) and in 2019 (N = 3) for AGN plants grown in Hershey and those harvested in October 2023 from the initial 2017 planting in the State College site (N = 5) for their pyranocoumarins, decursin (D) and decursinol angelate (DA). Both D and DA were detected in all root samples, with a majority (10/13) meeting and exceeding the Korean Pharmacopeia specification. The DA/D ratios in individual plants were consistent with those grown in Korea (<0.8) except one 3-year plant which yielded a ratio of 1.03. Therefore, AGN could be cultivated as a medicinal herbal crop upon horticultural optimization in PA and similar northern US states.

Supplementary Figure 1S from Potent Antiandrogen and Androgen Receptor Activities of an Angelica gigas–Containing Herbal Formulation: Identification of Decursin as a Novel and Active Compound with Implications for Prevention and Treatment of Prostate Cancer

Figure S1 shows A. Concentration-dependent reduction of number of adherent LNCaP cells exposed to increasing concentrations of bufalin for 96 h; B. Representative photomicrograph of LNCaP cells exposed to bufalin at 2 concentrations for 48 h. Figure S2 shows A, Western blot detection of c-PARP, AR, PSA in LNCaP cells exposed to bufalin for 48 h. B, Western blot detection of c-PARP, AR, PSA in LNCaP cells exposed to bufalin for 24 h. Figure S3 shows gross appearance of paraffin embedded tumors (3rd-8th ranked for each group) selected for biomarker analyses. Figure S4 shows Western blot detection of HK2 (hexokinase-2), p-AKT and AKT in tumors from vehicle- or bufalin-treated mice. PC3 cell extract and LNCaP extract (LN) were used as positive control for HK2 and active AKT (p-AKT), respectively. Figure S5 shows a schematic integration of bufalin induced cellular effects to inhibit LNCaP prostate tumor growth.

Supplemental Tables 1-7 and Supplemental Figures 1-5

TPS404 Background: There are currently no FDA approved modalities for intercepting biochemically recurrent prostate cancer (PCa) after standard of care surgery and radiation therapies to delay or prevent the need of androgen deprivation therapy (ADT) for localized disease. Preclinical modeling has suggested herbal alcoholic extracts of Angelica gigas Nakai (AGN) root, their signature pyranocoumarins and metabolite decursinol, as potential novel modalities to address this unmet clinical need. We hypothesize that CognI.Q at the higher doses has an acceptable safety profile in prostate cancer patients and pharmacokinetics (PK) exposure metrics will be increased proportional to dose increment. Methods: This is a single institution, phase 1 PK study, N=12. Primary objective- PK, pharmacodynamic (PD) biomarkers with a single ascending dose (SAD)-PK response design. After a subject is enrolled, a 14-day gap must occur before the next subject can be enrolled. If one subject develops a dose limiting toxicity (DLT) at any dose level, that subject will stop participation; If a 2nd subject develops DLT at the same dose level, the trial will be stopped, and the dose level below will be the maximum tolerated dose (MTD). Any subject at a higher dose level at the time of occurrence of 2nd DLT will also stop participation. All subjects will initially start at the 800 mg x 1dose, with further single dose escalation to 1200mg, 1600mg, 2000mg doses of AGN-CognI.Q; each dose will be 1-2 weeks apart. Inclusion criteria: Treated PCa, not on ADT; no active cancer. Subjects will be assessed for safety- clinical, labs (CBC, CMP, baseline and after 24hrs) and EKGs. PK blood will be taken at hourly intervals from 2-7hrs and 24hrs. Plasma pyranocoumarin content will be measured by LC-MS. Immunophenotyping of NK and T cell subtypes will be assessed at baseline and 24 h. Primary Endpoint: MTD. Secondary Endpoint: PK metrics; genotype CYP 2C19 and 3A4 metabolizer status and explore relationship to PK metrics and safety metrics; NK and inflammatory and immune cytokines as PD biomarkers. Trial is now open to accrual (Clinical trial registration NCT05375539). We anticipate that the acute dose safety and PK/PD information will inform the optimal design and execution of the longer-term safety and efficacy (phase I/II) trials. Research Support: MPI 1R01CA260901-01A. Clinical trial information: Clinical trial registration NCT05375539 .

Table S2 shows down-regulated genes by 10 nM bufalin over vehicle control by over 40% or more in LNCaP cells exposed for 24 h. Expressed as fold over vehicle control set as unity.

The novel selenium‐aspirin compound AS‐10 was recently reported by us with a cancer cell killing potency three orders of magnitude greater than aspirin in pancreatic cancer cell lines with caspase‐mediated apoptosis and a reasonable selectivity against malignant cells. Although we also observed its cytocidal activity against PC‐3 and DU145 androgen receptor (AR)‐negative and P53‐null/mutant aggressive human prostate cancer (PCa) cell lines in NCI‐60 screen, the potential involvement and targeting of AR and P53 pathways that are intact in early‐stage prostate carcinogenesis has not been examined, nor its primary molecular signaling after exposure.

The root of Angelica gigas [gigantus] Nakai (AGN) is a medicinal herbal in Korea. AGN root ethanolic extract dietary supplements are marketed for memory health and pain management. More than a dozen preclinical in vivo bioactivities of AGN extracts, including anti-cancer and sleep promotion, have been reported. Significant progress has been made in understanding the pharmacokinetics (PK) and metabolism of signature phytochemicals decursin and decursinol angelate and their botanical synthesis precursor and mammalian hepatic metabolite, decursinol, including human PK studies. This chapter summarizes PK and metabolism of pyranocoumarins and preclinical in vivo anti-cancer efficacy. For human clinical translation, significant challenges include sourcing of AGN extracts and product consistency. Human clinical trial design and AGN dose optimization are paramount in unlocking the anti-cancer potential. An open label Phase I/II trial is under way to estimate the effect size in a niche patient cohort with biochemically recurrent prostate cancer.

Lung cancer is the leading cause of cancer-related deaths due to its high incidence, late diagnosis, and limited success in clinical treatment. Prevention therefore is critical to help improve lung cancer management. Although tobacco control and tobacco cessation are effective strategies for lung cancer prevention, the numbers of current and former smokers in the USA and globally are not expected to decrease significantly in the near future. Chemoprevention and interception are needed to help high-risk individuals reduce their lung cancer risk or delay lung cancer development. This article will review the epidemiological data, pre-clinical animal data, and limited clinical data that support the potential of kava in reducing human lung cancer risk via its holistic polypharmacological effects. To facilitate its future clinical translation, advanced knowledge is needed with respect to its mechanisms of action and the development of mechanism-based non-invasive biomarkers in addition to safety and efficacy in more clinically relevant animal models.

Table S3 shows effect of bufalin on cyclins (CCN) and mini-chromosome maintenance (MCM) genes in LNCaP cells exposed for 24 h. Expressed relative to control set as unity.

Supplementary Figures 1-4 from Herbal Compound Farnesiferol C Exerts Antiangiogenic and Antitumor Activity and Targets Multiple Aspects of VEGFR1 (Flt1) or VEGFR2 (Flk1) Signaling Cascades

Effect of daily gavage of AGN or D/DA on weights of prostate lobes in TRAMP mice vs. wild type.