Abramson Cancer Center researchers have been studying the use of Hydroxychloroquine plus other drugs to look at whether dormant breast cancer cells can be prevented from recurring.
Fear of cancer recurrence, even in women whose breast cancer occurred many years ago, has prompted Penn Medicine researchers to launch the CLEVER study, in an attempt to treat remaining dormant cancer cells in the bone marrow.
Hydroxychloroquine as an anti-cancer agent
Do you remember Hydroxychloroquine, the drug that caused Democrats in the USA to ridicule Donald Trump over Covid? Well, Hydroxychloroquine actually does have significant health benefits and acts in many ways, including in cancer, where it blocks autophagy (a natural self-preservation mechanism that recycles damaged or dysfunctional parts of a cell and promotes cellular repair and survival).
In cancer, autophagy contributes to cancer cell regeneration and proliferation, It can also promote chemoresistance. Hydroxychloroquine is known to stop this. A meta-analysis showed that adding Hydroxychloroquine as an autophagy-inhibitor-based therapy to standard chemotherapy (and/or radiotherapy) had a better treatment response compared to chemotherapy or radiation therapy alone (1). This is because chemotherapy drugs such as Doxorubicin and 5FU after a number of rounds of use, increase autophagy and promote chemoresistance. Hydroxychloroquine (and Loratadine) are known to reduce this effect (2).
Tackling Autophagy in cancer
In a 2019 study, Everolimus was used in patients with previously treated Renal cancer. Everolimus is an mTOR inhibitor, but mTOR inhibitors (including even the off-label drug metformin) also appear to activate cancer-cell-protective autophagy. Knowing this, researchers added Hydroxychloroquine to block the autophagy, in a Phase I/II Clinical Trial. 22 out of 33 patients improved survival (3). The research showed that 600 mg of Hydroxychloroquine twice daily was a tolerable autophagy inhibitor. 10 mg of daily Everolimus was taken.
Everolimus is a Kinase inhibitor which also inhibits mTOR. Although it was known to induce autophagy, it was unknown whether everolimus-induced autophagy could make matters worse or whether it might play a critical role in its regulation of the cell cycle. 2019 research suggested it could cause cell cycle arrest via the degradation of Cyclin 1 (4).
The Clever study with Dormant breast cancer cells
Breast cancer recurrence may follow a dormant phase which can last several years. The ‘CLEVER study aimed to see if it was possible to kill off the dormant cells. The study was with TNBC patients all of whom had been lymph node positive, and had had active cancer within 5 years but were currently NED. Patients in the study had Everolimus, or Hydroxychloroquine, or both (5).
This was a feasibility study from the Abramson Cancer Center at Penn Medicine, seeking to anser the question, ‘Is it possible to target dormant cancer cells?’ These cells were felt to be dormant within bone tissue and all patients had first received a positive bone marrow test..
Of 184 patients, only 2 had recurrence. In 80% of patients, researchers felt the drugs identified dormant tumour cells and acted upon them. Their confidence level in using both drugs was 99.9 per cent. The trial continues, in order to measure survival times.
A $10 million fund then allowed the researchers to continue to monitor this research group. and also.to study Hydroxy with Abemaciclib instead to monitor residual disease in the bone marrow.
A review of the Abramson Cancer Center work and trials can be found here
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References
- The clinical value of using chloroquine or hydroxychloroquine as autophagy inhibitors in the treatment of cancers; Rari Xu et al; Medicine (Baltimore). 2018 Nov; 97(46): e12912.
- Inhibiting mTOR can paradoxically lead to decreased sensitivity to chemotherapy - my healing community
- Autophagy inhibition to augment mTOR inhibition: A phase I/II trial of everolimus and hydroxychloroquine in patients with previously treated renal cell carcinoma; Naomi B. Haas et al; Clin Cancer Res. 2019 Apr 1; 25(7): 2080–2087.
- Everolimus induces G1 cell cycle arrest through autophagy-mediated protein degradation of cyclin D1 in breast cancer cells; Guang Chen et al; Am J Physiol Cell Physiol. 2019 Aug 1;317(2):C244-C252.
- A phase II trial targeting disseminated dormant tumor cells with hydroxychloroquine, everolimus or the combination to prevent recurrent breast cancer (“CLEVER”); A DeMichele et al; Annals of Oncology; VOLUME 34, SUPPLEMENT 2, S281, OCTOBER 2023
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