Toward a Universal, Clinically Usable Theory of Mitochondrial Regulation of Advanced, Treatment-Resistant Carcinomas

Preprints.org · 2025-01-02

It has long been clear that mitochondria play important roles in metastatic disease, including regulatory contributions. Nonetheless, our knowledge in this area was too fragmentary to be of practical clinical use. However, over the last decade a robust community of investigators has extended our knowledge such that it is practical to begin to build testable theories. Moreover, these theories can plausibly give clinicians actionable opportunities to effectively attack advanced, currently treatment-resistant carcinomas. Our goal here is to contextualize and review important features of this recent new data base. We will also illustrate the kind of testable speculative theories that might be built on this foundation. Specifically, we will explore the evidence that many or most advanced, treatment-resistant tumors converge on a uniform state in which mitochondria play a universal, indispensable regulatory role (Figure 1 [1]). Speculative hypotheses of this form are robustly testable/falsifiable. Moreover, such theories suggest a specific novel approach to clinical attack on advanced, currently treatment-resistant carcinomas.

Toward a Unifying Hypothesis for Redesigned Lipid Catabolism as a Clinical Target in Advanced, Treatment-Resistant Carcinomas

International Journal of Molecular Sciences · 2023

• Cancer research
• Biology
• Bioinformatics

We review extensive progress from the cancer metabolism community in understanding the specific properties of lipid metabolism as it is redesigned in advanced carcinomas. This redesigned lipid metabolism allows affected carcinomas to make enhanced catabolic use of lipids in ways that are regulated by oxygen availability and is implicated as a primary source of resistance to diverse treatment approaches. This oxygen control permits lipid catabolism to be an effective energy/reducing potential source under the relatively hypoxic conditions of the carcinoma microenvironment and to do so without intolerable redox side effects. The resulting robust access to energy and reduced potential apparently allow carcinoma cells to better survive and recover from therapeutic trauma. We surveyed the essential features of this advanced carcinoma-specific lipid catabolism in the context of treatment resistance and explored a provisional unifying hypothesis. This hypothesis is robustly supported by substantial preclinical and clinical evidence. This approach identifies plausible routes to the clinical targeting of many or most sources of carcinoma treatment resistance, including the application of existing FDA-approved agents.

Evidence for a novel, effective approach to targeting carcinoma catabolism exploiting the first-in-class, anti-cancer mitochondrial drug, CPI-613

PLoS ONE · 2022 · 4 citations

• Biology
• Cancer research
• Cell biology

Clinical targeting of the altered metabolism of tumor cells has long been considered an attractive hypothetical approach. However, this strategy has yet to perform well clinically. Metabolic redundancy is among the limitations on effectiveness of many approaches, engendering intrinsic single-agent resistance or efficient evolution of such resistance. We describe new studies of the multi-target, tumor-preferential inhibition of the mitochondrial tricarboxylic acid (TCA) cycle by the first-in-class drug CPI-613® (devimistat). By suppressing the TCA hub, indispensable to many metabolic pathways, CPI-613 substantially reduces the effective redundancy of tumor catabolism. This TCA cycle suppression also engenders an apparently homeostatic accelerated, inefficient consumption of nutrient stores in carcinoma cells, eroding some sources of drug resistance. Nonetheless, sufficiently abundant, cell line-specific lipid stores in carcinoma cells are among remaining sources of CPI-613 resistance in vitro and during the in vivo pharmacological drug pulse. Specifically, the fatty acid beta-oxidation step delivers electrons directly to the mitochondrial electron transport system (ETC), by-passing the TCA cycle CPI-613 target and producing drug resistance. Strikingly, tested carcinoma cell lines configure much of this fatty acid flow to initially traverse the peroxisome enroute to additional mitochondrial beta-oxidation. This feature facilitates targeting as clinically practical agents disrupting this flow are available. Two such agents significantly sensitize an otherwise fully CPI-613-resistant carcinoma xenograft in vivo. These and related results are strong empirical support for a potentially general class of strategies for enhanced clinical targeting of carcinoma catabolism.

Progress on TRANSCEND Theme 1: Integrated Waste Management – 20194

2020

• Computer Science
• Business
• Process management

The New Human Science

2019-05-23 · 1 citations

Abstract 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.

Abstract 4861: Initial preclinical evaluation of a novel inhibitor of mitochondrial metabolism against prostate cancer

Cancer Research · 2018-07-01

Abstract 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.

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial

The Lancet Oncology · 2017-05-08 · 226 citations

Metabolic PET Imaging in Oncology

American Journal of Roentgenology · 2017-05-02 · 45 citations

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.

Abstract 2867: FDG-PET imaging as a potential biomarker of mitochondrial targeting by CPI-613, a novel inhibitor of mitochondrial metabolism

Cancer Research · 2017-07-01 · 1 citations

Abstract 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

What Can the Alabama Mississippians Teach Us About Human Evolution and Behavior?

Palgrave Macmillan US eBooks · 2017-01-01

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. Over the course of the Scientific Revolution of the last 400 years, we have had many occasions to watch individual sciences mature. They pass through a predictable series of steps or stages. A new science begins with what is sometimes called “natural history,” the careful description of the phenomena to be described. The growth into a mature science follows. This is when coherent theory, unifying the entire field of study, is developed. We have also learned that this transition from natural history to maturing science always involves unification with other sciences whose insights provide indispensable explanatory components to the emerging newer science.