ETODOLAC

Etodolac is a nonsteroidal anti-inflammatory drug, frequently prescribed to reduce symptoms of arthritis. It works by suppressing a certain enzyme in the body which plays a key role in driving inflammatory responses (COX-2) and is shown to increase cancer progression. Many drugs in the NSAID and other categories have failed to show any clinical evidence in oncology despite a significant number of trials (see references). An notable exception, for some cancer types, is the combination of etodolac with beta-blocker propranolol where emerging promising and striking benefits are shown in pilot clinical trials.

In particular a pilot study in colorectal cancer from 2023 showed radically improved disease free progression for post-surgery colorectal cancer patients . The same team showed earlier that this drug combination resulted in significantly lowered biomarkers of metastatic activity in colorectal cancer surgery, and increased natural killer immune cell responses. Additional data was also produced in post surgery studies for early phase breast cancer in a phase II trial (Highlights 1,2,3)

Ongoing studies include the PROSPER pancreatic cancer clinical trial, where etodolac-proproanol is seen as a viable candiate protocol. The pilot phase has failed to meet recruitment goals but the preliminary data indicated large reductions in progression risk including mush lower metastatic spread, confirmed in a variety of disease related bio-markers in patients. The PRESERVE trial onging in ovarian cancer therapy is looking at etodolac for stress reduction

The results of this pilot study suggest that pharmacological suppression of adrenergic and inflammatory signaling is readily feasible using re-purposed safe and available marketed drugs, and may significantly reduce the risk for post-surgical CRC recurrence. These results underscore the need and scientific justification for larger studies. Importantly, pharmaceutical companies have little incentive to conduct clinical studies employing off-patented drugs (such as etodolac and propranolol)

..this clinical trial is the first to investigate the combined perioperative inhibition of β-adrenoceptors and COX2 in patients with CRC. The outcomes indicate a favorable impact on molecular biomarkers associated with tumor growth and metastatic disease. We recently observed similar favorable effects of a similar drug treatment regimen on biomarkers in patients with breast cancer, which strengthens the relevance and generalizability of the current findings. Overall, our findings indicate that the perioperative propranolol/etodolac protocol is e...

However, one could even argue that the pathology results were to the disadvantage of the verum group, since there were even two non-malignant cases in the placebo group and one patient with previously undetected liver metastases that could not be curatively resected in the verum group. Both, median overall and disease-free survival were longer in the verum group, but probably the most notable difference was the difference in distant recurrences with 54.5% in the placebo group and 11.1% in the verum group. This is supportive to the underlying mech...

Exploratory analyses of transcriptome modulation in PBMCs revealed treatment-induced improvement at T2/T3 in several transcription factors that in primary tumors indicate poor prognosis (CUX1, THRa, EVI1, RORa, PBX1, and T3R), angiogenesis (YY1), EMT (GATA1 and deltaEF1/ZEB1), proliferation (GATA2), and glucocorticoids response (GRE), while increasing the activity of the oncogenes c-MYB and N-MYC. Overall, the drug treatment may benefit breast cancer patients through reducing systemic inflammation and pro-metastatic/pro-growth biomarkers in the e...

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https://www.sciencedirect.com/science/article/abs/pii/S0748798322007053	4	Between May 2010 and March 2015, 34 patients newly diagnosed with colorectal cancer, without evidence of metastasis, undergoing surgery were randomised to receive oral propranolol and etodolac (n=16) or placebo (n=18). The 20-day treatment regimen was initiated five days before surgery and ended two weeks after surgery. Results of the intent-to-treat analysis at five years follow-up showed that 12.5% (2/16) patients in the propranolol and etodolac arm versus 50% (9/18) in the placebo arm experienced recurrence, and that 12.5% (2/16) patients died in the propranolol and etodolac arm versus 22% (4/18) in the placebo arm).	For patients who adhered to the protocol, 0% (0/11) patients in the treatment group versus 47% (8/17) in the placebo group exhibited recurrence (P=0.007), and 0% (0/11) in the treatment group versus 17.6% (3/17) in the placebo group died . Mean disease-free survival (DFS) was 53.3 months in the treatment arm versus 40.65 months in the control arm. Adverse events were equivalent between the two groups.
https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.32950	3.5	This clinical trial is the first to investigate the combined perioperative inhibition of β-adrenoceptors and COX2 in patients with CRC. The outcomes indicate a favorable impact on molecular biomarkers associated with tumor growth and metastatic disease. We recently observed similar favorable effects of a similar drug treatment regimen on biomarkers in patients with breast cancer,18, 27 which strengthens the relevance and generalizability of the current findings. Overall, our findings indicate that the perioperative propranolol/etodolac protocol is empirically safe, easy to administer, and inexpensive and has overall favorable molecular impacts on tumor tissues. These findings also provide a strong rationale for future clinical trials in larger samples to assess the impact of this protocol on clinical endpoints such as disease recurrence and survival.	This study was not designed or powered to assess drug effects on disease recurrence and survival, though we did collect data on 3-year recurrence rate to assess long-term safety. The results revealed a favorable trend toward reduced CRC recurrence in treated patients. Specifically, in protocol-compliant patients, metastases occurred in 0 of 11 patients who received drug treatment versus 5 of 17 patients who received placebo (P = .063). Kaplan-Meier survival analysis (log-rank test for recurrence at 3-year follow-up) showed a marginally significant (P = .054) reduction in recurrence (Fig. 4B). In intent-to-treat patients, the same analysis indicated a nonsignificant trend toward reduced recurrence in patients who received drug treatment (2/16) versus patients who received placebo
https://pmc.ncbi.nlm.nih.gov/articles/PMC5559335/	3.5	These data show that perioperative administration of the β-adrenergic antagonist propranolol and the COX-2 inhibitor etodolac induces multiple favorable impacts on (i) primary tumor gene expression profiles (bioinformatic indications of reduced EMT; reduced activity of GATA-1, GATA-2, EGR3, GRE, and STAT3 transcription factors; and reduced tumor-associated monocytes and increased tumor-associated B cells) and on (ii) circulating immune parameters (serum and ex vivo-induced cytokine levels, reduced classical monocyte influx, and increased NK cell activation markers). Each of these outcomes has previously been linked to reduced tumor progression	IL-6 and CRP are associated with tumor progression and poor prognosis in multiple solid tumor types, including breast, lung, and prostate, and hematopoietic malignancies (37,45). IL-6 activates the janus-kinase-STAT signaling pathway, which is well known to promote tumor cell proliferation, survival, and invasion, as well as immunosuppression and inflammation. STAT3 and STAT5 are strongly associated with cancer progression (37). Here, both plasma IL-6 levels and indicators of tumor STAT3 activity were reduced by the drug treatment. Drug treatment also effectively blocked a marked postoperative (T3) mobilization of “classical” pro-inflammatory CD14++CD16− monocytes
https://www.sciencedirect.com/science/article/abs/pii/S0889159118301879?via%3Dihub	3.5	Results based on a-priori hypotheses indicated that already before surgery (T2), serum levels of pro-inflammatory IL-6, CRP, and IFNγ, and anti-inflammatory, cortisol and IL-10, increased. At T2 and/or T3, drug treatment reduced serum levels of the above pro-inflammatory cytokines and of TRAIL, as well as activity of multiple inflammation-related transcription factors (including NFκB, STAT3, ISRE), but not serum levels of cortisol, IL-10, IL-18, IL-8, VEGF and TNFα.	Exploratory analyses of transcriptome modulation in PBMCs revealed treatment-induced improvement at T2/T3 in several transcription factors that in primary tumors indicate poor prognosis (CUX1, THRa, EVI1, RORa, PBX1, and T3R), angiogenesis (YY1), EMT (GATA1 and deltaEF1/ZEB1), proliferation (GATA2), and glucocorticoids response (GRE), while increasing the activity of the oncogenes c-MYB and N-MYC. Overall, the drug treatment may benefit breast cancer patients through reducing systemic inflammation and pro-metastatic/pro-growth biomarkers in the excised tumor and PBMCs.
https://aacrjournals.org/clincancerres/article/17/11/3803/12036/Randomized-Double-Blind-Trial-of-Sulindac-and	3	Further, the relatively high proportion of polypectomized subjects compared with polyp-free subjects was probably because of their higher motivation to participate in the current trial. Nevertheless, the results of the 2-month treatment on ACF both in comparison analysis among groups (Table 2) and in the intragroup analysis (Supplementary Table S1) clearly indicated the effectiveness of sulindac in eradicating the lesions, particularly in polypectomized subjects. Thus, the primary endpoint of the present study was achieved. The failure of etodolac to eradicate ACF is probably explained by the fact that most ACF do not express COX-2 (20). Moreover, it is surmised that in short-term treatment etodolac, which could not eradicate ACF, was ineffective in suppressing polyp development whereas sulindac was able to inhibit incidence of polyp 1 year after the initiation of treatment by eradicating ACF with short-term treatment	Results showing in both analyses of the number and incidence of adenoma or total polyps either a significant or marked (marginal) reduction in the sulindac group strongly suggest not only the effectiveness of short-term treatment with sulindac in suppressing polyp occurrence but also the utility of ACF as precursor lesions for polyps although the possibility that the reduction in ACF was indirectly related to that of polyp occurrence cannot be completely denied. This notion was further supported by results of the analysis of responders versus nonresponders that showed significantly fewer polyps in the former than in the latter subjects in the sulindac group. Moreover, the average polyp size in the sulindac group was smaller than in the placebo group, although without statistical significance
https://pmc.ncbi.nlm.nih.gov/articles/PMC4618628/	2	A major strength of our approach is its potential clinical relevance. By conducting this biomarker study in patients with breast cancer, we have, by definition, controlled for the tumor microenvironment, pharmacokinetics of study drug, and other unknown factors which can generate misleading results in model systems 25. To the best of our knowledge, this is the first clinical observation of a COX-2 increase in gene expression with etodolac treatment. Notably, feedback gene expression upregulation has been reported with other inhibitors such as a BRAF inhibitor which causes upregulation of EGFR gene expression in colon cancer, in this case leading to therapeutic resistance.	We also observed an increase in COX-2 pathway (COX-2 and possibly β-catenin) gene expression after etodolac exposure. Although etodolac is a well-known selective COX-2 enzymatic inhibitor 17, compensatory increased gene expression of COX-2 with NSAIDs has been reported in the past 21,22. Additional study, such as analysis of prostaglandin E2 levels, will be required to determine if the increased gene expression level of COX-2 after etodolac exposure is associated with preserved enzymatic activity. Our results for COX-2 demonstrate the need for optimized biomarkers to monitor the effect of agents that may be subject to compensatory responses. The compensatory effect seen in this study may partially explain why previous studies evaluating NSAIDs in breast cancer prevention have had conflicting results
https://www.tandfonline.com/doi/full/10.2217/fon-2017-0635	N/A	Given pre-clinical and clinical observations described above, we believe that cancer mortality could be reduced by a safe perioperative blockade of SIRs. It is now justified and crucial to conduct larger clinical trials, assessing disease-free survival (DFS) and overall survival (OS), as without these long-term outcomes such interventions will not become a clinical routine. However, recruiting funds for such large trials is an ongoing challenge, as drugs that can be used for this purpose (e.g., propranolol and etodolac) are not patented and are inexpensive, and thus such trials are unattractive for pharmaceutical companies. Unfortunately, propranolol and/or etodolac are contraindicated for approximately 50% of patients (mostly due to asthma, cardiovascular disease, diabetes or low blood pressure). Therefore, the development of alternative approaches to limit perioperative SIRs is required	Catecholamines (CAs) and prostaglandins (PGs; specifically PGE2), which are abundant perioperatively, were repeatedly shown to mediate numerous pro-metastatic effects of stress and surgery, through various mechanisms [Citation2,Citation7]. For example, these ligands were shown to regulate the secretion of pro- and anti-inflammatory soluble factors (e.g. IL-6, CRP, TNF-α and IL-10), locally and systemically, to suppress NK and T-cell cytotoxicity, thus promoting cancer metastasis [Citation2], and to directly impact tumor cells, promoting their growth, motility, resistance to cell death (apoptosis and anoikis), epithelial-to-mesenchymal transition [Citation8] and secretion of pro-angiogenic and pro-metastatic factors (e.g., VEGF, MMP2, MMP9) . Recently, neuroendocrine stress responses were also suggested to promote an escape from dormancy of cancer cells
https://pmc.ncbi.nlm.nih.gov/articles/PMC10943275/	N/A	In this systematic review, between 2000 and 2023, most of the 67 randomized controlled trials evaluating the efficacy of cardiovascular and anti‐inflammatory drugs in treating or preventing recurrence of cancer did not demonstrate clinical benefit. In fact, three studies demonstrated worse progression‐free survival or overall survival. Only two small studies demonstrated an improvement in overall survival for advanced/metastatic non‐small‐cell lung cancer and advanced hepatocellular carcinoma. The patient population from the two small positive trials composed a small portion (0.7%, 210/28,266) of the total patient population among all randomized controlled trials. There was a relatively equal distribution of the type of cardiovascular drug used (NSAID versus statin versus metformin) used in these clinical trials	Despite promising pre‐clinical and observational data involving cardiovascular drugs and anti‐inflammatory drugs in treating cancer or preventing cancer recurrence, randomized controlled trial data have thus far not demonstrated the previously anticipated improvement in survival or risk reduction in recurrence. While the biological plausibility for anti‐cancer effect may be present as shown by pre‐clinical studies, it is possible that current anti‐cancer therapies such as chemotherapy and radiation are effective at disrupting specific pathways that are more influential in tumorigenesis than the pathways acted upon by cardiovascular drugs and anti‐inflammatory drugs. As such, the effect of cardiovascular and anti‐inflammatory drugs may be less significant and not translate to clinical benefit as demonstrated by this systematic review and meta‐analysis.
https://pmc.ncbi.nlm.nih.gov/articles/PMC12098435/	3.5	Both, median overall and disease-free survival were longer in the [pancreatic cancer] verum group, but probably the most notable difference was the difference in distant recurrences with 54.5% in the placebo group and 11.1% in the verum group. This is supportive to the underlying mechanistic rationale of the trial intervention that the protumorigenic/prometastatic effect caused by an excess release of catecholamines and prostaglandins in the perioperative period can be effectively inhibited by propranolol and etodolac	However, trial treatment seemed to cause a more rapid normalization of post-operative systemic inflammation in terms of faster normalization of IL-6 and mitigation of post-operative loss of immune effectors. Additionally, the quantification of immune cells in the tumor microenvironment was indicative of a modification of the local immune milieu towards increased peritumoral inflammation.

ETODOLAC

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