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OBJECTIVE. In this article, we provide a general overview of how cancer cells subvert critical metabolic pathways to support their growth and unchecked division. Furthermore, we outline how molecular imaging can diagnostically exploit the resulting differences between cancer and normal cells. CONCLUSION. Molecular PET can provide valuable information about the metabolic dysregulation in cancer.

Summary Background Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. Methods In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0–1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m 2 , leucovorin at 400 mg/m 2 , irinotecan at 140 mg/m 2 , and fluorouracil 400 mg/m 2 bolus followed by 2400 mg/m 2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m 2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Findings Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m 2 . The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4–19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250–602). Two patients enrolled at a higher dose of 1000 mg/m 2 , and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3–4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3–4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1–3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. Interpretation A maximum tolerated dose of CPI-613 was established at 500 mg/m 2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Funding Comprehensive Cancer Center of Wake Forest Baptist Medical Center.

All prior attempts to understand human origins, behavior, and history have led to paradoxes and dilemmas, highly resistant to resolution. This chapter reviews specific cases of failures to resolve these apparent paradoxes and dilemmas in human evolution and the social sciences. The authors argue that these failures are rooted in confusing proximate with ultimate causation. They further argue that a sound theory of human origins, behavior, and history (social coercion theory) can help to understand the human condition scientifically; specifically, this theory argues that all the unique properties of humans emerge from the unprecedented human social evolution, driven, in turn by the evolution of cost-effective coercive management of conflicts of interest. Finally, the authors argue that social coercion theory yields the first general theory of history, economics, and politics, which provides an approach to problems within the social sciences while armed with a grasp of ultimate causation. Consequently, formerly intractable scientific questions and social concerns become manageable and solvable.

It is an exciting time in the scientific study of humans and our evolution. The archaeology of Alabama provides particularly powerful insights and empirical evidence adding much to this study. The “new human sciences” are maturing at an ever-accelerating rate from a series of relatively isolated disciplines (including psychology, biology, paleontology, archaeology, anthropology, economics, and history) into a single powerfully insightful “human” science. Moreover, this growing clarity and confidence, in turn, allows us to choose specific opportunities for fruitful study—and Alabama offers an especially elegant case.

CPI-613 is a novel inhibitor of mitochondrial metabolism that has recently shown promise in early stage clinical trials for pancreatic cancer, lymphoma, and leukemia. It is a lipoate analogue that selectively inhibits pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH) complexes in tumor cells (reviewed in Exp.Rev.Clin.Pharma. 7, 837). Since these two enzymes control the vast majority of carbon flow into the tricarboxylic acid (TCA) cycle, CPI-613 significantly inhibits mitochondrial metabolism. Importantly, it has demonstrated a favorable safety profile in clinical trials, presumably due to its documented selectivity to cancer metabolism. Early phase clinical trials with CPI-613 have demonstrated very promising clinical responses in pancreatic cancer, leukemia, and lymphoma when used in combination with standard chemotherapy. For example, in a recently published Phase I clinical trial in 18 patients with Stage 4 pancreatic cancer in combination with a modified FOLFIRINOX regiment, three (17%) had a complete response, eight (44%) had a partial response, three (17%) had stable disease, and four (22%) had progressive disease. Since altered cancer metabolism is a hallmark of cancer in general, we hypothesized that CPI-613 should have efficacy in other cancers, including prostate cancer, which is the second most common malignancy in men that affects over 160,000 men in the U.S annually. To test our hypothesis, we treated prostate cancer cell lines with CPI-613 in vitro and in vivo in a preclinical murine flank model. We found that CPI-613 was highly effective at killing prostate cancer cells in vitro, which was similar to its previously published potency in pancreatic cancer cells. Furthermore, we found in vitro therapeutic synergy with docotaxel, a standard of care treatment of advanced prostate cancer. We therefore tested CPI-613 in a preclinical Pc-3 flank model of androgen-resistant prostate cancer. Groups of mice (n=8) were treated 2-3 times per a week for 5 weeks with 2.5mg/kg of CPI-613, 10mg/kg of CPI-613 and control saline after tumors reached approximately 40mm3. CPI-613 was formulated in the same manner as it was for clinical trials. Both groups of mice treated with CPI-613 demonstrated a significant decrease in tumor growth without any toxicity. There was no observed difference between doses, which may be due to having crossed the threshold of drug uptake and concentration required in the mitochondria for a response. Furthermore, there was a significant increase in survival between treated groups and the control group, again without a dose effect. These results for the first time indicate biological activity of CPI-613 both in vitro and in vivo against prostate cancer and therefore warrants further investigation in representative preclinical prostate cancer models and in combination with standard-of-care therapies. Citation Format: Kiran K. Solingapuram Sai, Anirudh Sattiraju, Zuzana Zachar, Michael S. Dahan, Robert Shorr, Timothy S. Pardee, Paul M. Bingham, Akiva Mintz. Initial preclinical evaluation of a novel inhibitor of mitochondrial metabolism against prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4861.

CPI-613 is a lipoate analogue that has been shown to inhibit the pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH) complexes selectively in tumor cells (reviewed in Exp.Rev.Clin.Pharma. 7, 837). These two enzymes control the vast majority of carbon flow into the tricarboxylic acid (TCA) cycle and play a central role in mitochondrial metabolism. PDH converts pyruvate into acetyl-CoA, which in turn can enter the TCA cycle for cellular respiration. Since pyruvate is the final product of glycolysis, PDH serves to link glycolysis to the TCA cycle. Early clinical trials with CPI-613 have demonstrated very promising clinical responses in pancreatic cancer, leukemia, and lymphoma when used in combination with standard chemotherapy. Moreover, apparently homeostatic responses of tumor cells to CPI-613 inhibition of mitochondrial metabolism include compensatory upregulation of glucose uptake. Thus, we hypothesized that we can use 18F-Fludeoxyglucose (FDG)-PET/CT, a translational imaging approach that measures cellular glucose uptake, as a biomarker for CPI-613 cellular delivery and its targeting of mitochondrial metabolism. Therefore, in this work we evaluated the in vitro and in vivo glucose uptake in cancer cells and tumor xenografts after treatment with CPI-613. To measure glucose uptake in vitro we pulsed BxPc3 pancreatic cancer cells with 3H 2-deoxyglucose for 15 or 60 minutes following 2 hours of treatment with CPI-613. We observed a significant upregulation (~100% increase) of cellular 2-deoxyglucose uptake, consistent with a compensatory increase in glucose uptake as a result of successful targeting of mitochondrial metabolism. We therefore examined whether this upregulation occurs in vivo using FDG-PET/CT. Mice bearing BxPc3 flank tumors were treated with 50mg/kg of CPI-613 and underwent FDG-PET/CT scans 4 hours and 24 hours post-CPI-613 treatment. Similar to the in vitro response, tumors treated with CPI-613 exhibited a 75% increase in 18F-FDG uptake compared to untreated controls at 4 hours post therapy. In the 24 hour post-therapy scans, tumor 18F-FDG was significantly decreased, indicating tumor cell killing, which corresponds to previously published data that demonstrated efficacy of CPI-613 against BxPc3 tumor xenografts. These results indicate the potential for using the initial FDG flare seen on PET imaging as a biomarker to detect mitochondrial targeting by CPI-613 immediately after CPI-613 treatment, a strategy that may be used, after further clinical validation, to stratify responders to this novel mitochondrial inhibitor. Citation Format: Kiran Solingapuram Sai, Zuzana Zachar, Frankis Almaguel, Shawn D. Stuart, Michael S. Dahan, Moises Guardado, Stephanie Rideout, Minghui Wang, Anirudh Sattiraju, Paul M. Bingham, Boris Pasche, Akiva Mintz. FDG-PET imaging as a potential biomarker of mitochondrial targeting by CPI-613, a novel inhibitor of mitochondrial metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2867. doi:10.1158/1538-7445.AM2017-2867

We will describe recent progress in understanding the role of cancer metabolic remodeling in determining the response of tumors and tumor cells to a novel, first-in-class clinical agent class selectively targeting cancer cell mitochondrial metabolism. The reconfiguration of mitochondrial metabolism in cancer in general, and the tricarboxylic acid (TCA) cycle in particular, presents a rich source of potential therapeutic targets. Pyruvate dehydrogenase (PDH) and alpha ketoglutarate dehydrogenase (KGDH) are two gatekeeper enzymes regulating carbon flux into the mitochondrial TCA cycle. A key component of the altered regulatory processes in cancer is lipoic acid (lipoate), which not only functions as a cofactor for both PDH and KGDH, but also as source of regulatory information. Moreover, the lipoate-sensitive regulatory components of PDH and KGDH are substantially reconfigured in tumor cells, providing cancer-specific targets that can be successfully attacked with properly designed lipoate analogs. We developed and characterized CPI-613, a lipoic acid analog, which selectively targets mitochondrial metabolism in tumor cells by mobilizing lipoate-sensitive, cancer-specific regulation of PDH and KGDH, shutting down the two enzymes and thereby choking carbon flow through the TCA cycle. This attack on mitochondrial metabolism redundantly activates multiple cell death pathways (Zachar, et al., 2011, J Mol Med 89, 1137; Stuart, et al., 2014, Cancer&Metab 2, 4). In vitro, CPI-613 is uniformly effective in killing tumor cell lines (more than 50 tumor lines tested to date). Moreover, these drugs have produced compelling clinical responses (including complete remissions) in some, but not all patients with advanced, refractory, heavily pre-treated cancers in initial Phase I/II clinical trials (Pardee et al., 2014, Clin Cancer Res 20:5255). In an effort to explore the mechanisms of CPI-613 activity and characterize the reasons for differential patient responses, we have shown that the kinetics of the cancer cell death response to CPI-613 is profoundly affected by the carbon sources available to the cell (Zachar, et al., 2011, J Mol Med 89, 1137). For example, in media where pyruvate and glutamine (capable of producing net ATP synthesis only in the mitochondrial compartment) are the major carbon sources, death is rapid, completed within 4 hours (op cit). In contrast, when glucose is substituted for pyruvate, the cell death programs take up to 48 hours to complete. We have analyzed the mechanistic basis of this and related observations, including steady state and flux metabolomics, pharmacological inhibitors of non-TCA metabolic pathways, and manipulation of media composition to systematically characterize these dramatic effects of nutrient availability on cancer cell drug response. Our results demonstrate that CPI-613 induced inactivation of tumor cell KGDH is modulated by the potency of mitochondrial redox detoxification (Stuart, et al., 2014, Cancer&Metab 2, 4). Given that various metabolic pathways (for example, glycolysis) can ultimately contribute to mitochondrial ROS detoxification potential, it appears that substrate availability powerfully influences the cellular response to CPI-613. These insights open a number of fundamentally new approaches to increasing the fraction of patients who respond strongly to CPI-613 in the clinic. We will also report pre-clinical studies targeted at allowing planned future clinical trials to exploit these new insights. Citation Format: Shawn D. Stuart, Moises Guardado, Michael Dahan, Paul M. Bingham, Zuzana Zachar. Tumor metabolic remodeling can modulate anticancer drug response: CPI-613 attack on tumor cell mitochondrial metabolism is mediated by metabolite availability. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A61.