DOXYCYCLINE

There is some early evidence in breast cancer that pre-surgery treatment with doxycline can suppress 2 key markers of cancer stem cell activity. (Highlight 1). More advanced trials under the name NEODOXy are in pre-recruitment.

On the other hand, a phase II trial looking at bone metastases in breast cancer showed no evidence of effects, but induced considerable toxcity in patients worsening their quality of life. Some clinical trials have been withdrawn. Another recent clinical trial demonstrated no improvements in overall survival rates despite confiming suppression of some key markers known to increase metastatic breast cancer progression (Highlights 2&3). As a broad spectrum antibiotic, effects on microbiome can be incredibly debilitating. Use of antibiotics has been seen to dramatically worsen relative survival rates in lung cancer immunotherapy therapy for instance (see akkermansia in the Supplements Library). There are some effects to develop new drugs from doxycyline that lack antibiotic activity and have better uptake.

There are ongoing trials with metformin looking to understand and develop future targeting https://clinicaltrials.gov/study/NCT02874430 , clearly any use of these drugs has to be under your oncologist. Many of the targeted anti cancer activities can be helped with a largely plant based diet. Walnuts, berries, soy, flax and green tea or coffee as well as supplements like pomegranate or urolithin-a may help in these areas while bringing anti-inflammatory, midrobiota enhancing and metabolic health.

Quantitative decreases in CD44 and ALDH1 expression are consistent with pre-clinical experiments and suggest that doxycycline can selectively eradicate CSCs in breast cancer patients..CD44 levels were reduced between 17.65 and 66.67%, in 8 out of 9 patients treated with doxycycline. In contrast, only one patient showed a rise in CD44, by 15%. Overall, this represents a positive response rate of nearly 90%. Similar results were also obtained with ALDH1, another marker of stemness. In contrast, markers of mitochondria, proliferation, apoptosis, and...

This is the largest study to date evaluating the effects of doxycycline in bone-metastatic breast cancer patients. Doxycycline daily for 12 weeks did not appear to significantly enhance palliative benefit nor change bone resorption markers…Out of 37 patients, 16 (43%) had GI adverse events (nausea, vomiting and/or heartburn), and this became limiting for 7 of these patients requiring them to come off study early. Once GI toxicity started it was our clinical impression that it persisted despite lowering the dose of doxycycline…The medi...

Statistically significant associations were observed between MMP2, MMP9 and TIMP2 at baseline with significant associations maintained between absolute levels and changes in levels of MMP2 and TIMP2 at weeks 4–12 post initiation of doxycycline. Treatment with doxycycline generally resulted in decreases in MMP2 and MMP9 levels with concurrent upregulation of TIMP2 at 12 weeks post-initiation of doxycycline treatment. Despite this, we observed no association with the levels of any of these factors with either SRE-free or overall survival in this ...

Our results suggest that doxycycline doses as low as 100 mg once daily are efficacious and well tolerated for the prevention of skin toxicity in patients with mCRC [advanced colorectal cancer] who undergo treatment with chemotherapy plus EGFR-targeted therapies…A total of 60.0% and 20.8% of patients who received doxycycline 50 mg/day and 100 mg/day, respectively, had at least one ≥ grade 2 skin toxicity. Patients treated with doxycycline 100 mg once daily experienced less QoL deterioration. Only 1 patient reported a mild doxycycline-relat...

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URL	Rating	Highlight	Highlight 2
https://pmc.ncbi.nlm.nih.gov/articles/PMC6194352/	3.5	Importantly, most biomarkers tested remained unchanged, with the exception of CD44, which was reduced on average by nearly 40%, in a period of only two weeks of treatment. Analysis of waterfall plot data revealed that in 8 out of 9 patients treated with doxycycline, CD44 levels were reduced between 17.65 and 66.67%. In contrast, only one patient showed a rise in CD44, by 15%. Two patients of the HER2(+) sub-type, also showed positivity for another stem cell marker, namely ALDH1. In these HER2(+) patients, ALDH1 levels were reduced by nearly 60% in one patient, while ALDH1 levels were reduced by 90% in the other patient, in response to doxycycline. Thus, oral doxycycline treatment effectively reduced the expression of two CSC markers, in early breast cancer patients.	Post-doxycycline tumor samples demonstrated a statistically significant decrease in the stemness marker CD44 (p-value < 0.005), when compared to pre-doxycycline tumor samples. More specifically, CD44 levels were reduced between 17.65 and 66.67%, in 8 out of 9 patients treated with doxycycline. In contrast, only one patient showed a rise in CD44, by 15%. Overall, this represents a positive response rate of nearly 90%. Similar results were also obtained with ALDH1, another marker of stemness. In contrast, markers of mitochondria, proliferation, apoptosis, and neo-angiogenesis, were all similar between the two groups.
https://www.sciencedirect.com/science/article/pii/S2212137416300197	N/A	This is the largest study to date evaluating the effects of doxycycline in bone-metastatic breast cancer patients. Doxycycline daily for 12 weeks did not appear to significantly enhance palliative benefit nor change bone resorption markers. The toxicity profile of doxycycline in this patient population will make further evaluation challenging.	Toxicity was significant and limiting in this patient population. Drug toxicity was by far the most common reason for patients failing to complete treatment. Out of 37 patients, 16 (43%) had GI adverse events (nausea, vomiting and/or heartburn), and this became limiting for 7 of these patients requiring them to come off study early. Once GI toxicity started it was our clinical impression that it persisted despite lowering the dose of doxycycline. As part of an ad hoc analysis we decided to evaluate the time to development of GI toxicity. The median (and range) of time from starting the doxycycline to development of GI toxicity was 9 days
https://www.mdpi.com/2072-6694/15/3/571	N/A	Statistically significant associations were observed between MMP2, MMP9 and TIMP2 at baseline with significant associations maintained between absolute levels and changes in levels of MMP2 and TIMP2 at weeks 4–12 post initiation of doxycycline. Treatment with doxycycline generally resulted in decreases in MMP2 and MMP9 levels with concurrent upregulation of TIMP2 at 12 weeks post-initiation of doxycycline treatment. Despite this, we observed no association with the levels of any of these factors with either SRE-free or overall survival in this patient cohort. In summary, despite observing hypothesized effects of doxycycline administration on surrogate markers of its anti-tumor activity, measures of circulating levels of these biomarkers were not prognostic in this patient population.	TIMP2 is a known inhibitor of MMP activity and tumor growth that has been shown to be reciprocally downregulated with MMP2 upregulation . As such, we evaluated circulating levels of MMP2, MMP9 and TIMP2 as indicators of doxycycline activity in patients enrolled in the Achilles trial. As hypothesized, we generally observed decreases in MMP2 and MMP9 levels and increases in TIMP2 levels in patients following doxycycline administration, suggesting that the dosing regimen reached effective levels in patients. We also observed a significant association between MMP2 and TIMP2 levels as would be predicted based on previous literature suggesting their reciprocal co-regulation Despite this, we did not observe any significant relationship with the clinical parameters of SRE-free or overall survival.
https://pubmed.ncbi.nlm.nih.gov/35776185/	2	Our results suggest that doxycycline doses as low as 100 mg once daily are efficacious and well tolerated for the prevention of skin toxicity in patients with mCRC who undergo treatment with chemotherapy plus EGFR-targeted therapies.	A total of 60.0% (95% CI 29.6–90.0) and 20.8% (95% CI 4.6–37.0) of patients who received doxycycline 50 mg/day and 100 mg/day, respectively, had at least one ≥ grade 2 skin toxicity. Patients treated with doxycycline 100 mg once daily experienced less QoL deterioration. Only 1 patient reported a mild doxycycline-related gastrointestinal adverse event.

DOXYCYCLINE

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