Targeted therapies (including hormone therapies) and treatments which modulate or prime the immune system to attack cancer (i.e., immunotherapies) are fast becoming an important and effective treatment option for some types of cancer.
Targeted cancer treatments aim to block specific, directly ‘targeted’ molecules and signals which cancer cells use to grow, repair damage, and survive. These types of treatments include tyrosine kinase inhibitors (TKIs), proteasome inhibitors, mTOR inhibitors, MEK inhibitors, HDAC inhibitors, PARP inhibitors, PI3K inhibitors, hormonal therapies, and anti-angiogenic treatments (which block the growth of tumor-feeding blood vessels).
Monoclonal antibodies are also a type of targeted therapy. They are engineered to attach to specific proteins on the cancer cell and damage cancer cells either directly, or via improved targeting of other therapies. Some monoclonal antibodies are also immunotherapies.
Though effective, targeted therapies and immunotherapies can vary in efficacy for individual patients and may also be associated with the development of treatment-resistant disease. Consequently, researchers are very interested in finding ways to enhance and prolong the effectiveness of these treatments. Combining multiple targeted treatments is one well understood way of helping to reduce resistance developing (Lopez and Banerji, 2017).
In the context of treatment delivered at Care Oncology, it is critically important to understand the safety considerations when administering our protocol medications alongside immunotherapies and targeted therapies. While many of the latter agents are still “new” (i.e., approved in the last 5‑10 years), the COC protocol drugs have been widely prescribed for many decades. We can therefore refer to an established and ever-growing body of drug-drug interaction data. Each patient is carefully assessed at the commencement of treatment and subsequently monitored regularly.
Immune-targeted therapies work by enabling our immune system to better recognize and target cancer cells, and by helping to optimize the quality of the immune response against cancer cells.
Emerging evidence suggests the COC Protocol medications may help to metabolically optimize cancer-fighting immune cells, as well as the microenvironment surrounding the tumor cells. This action can help to boost both the body’s innate anticancer immune response, and also potentially the action of novel immunotherapies (Bahrambeigi and Shafiei-Irannejad, 2019; Eikawa et al., 2015; Guerini et al., 2019; Kurelac et al., 2019; Mira et al., 2013).
Checkpoint inhibitor therapies
‘Checkpoint inhibitor’ immunotherapies aim to block signals which cancer cells use to suppress immune system T cells from attacking them. However, for some patients this type of immunotherapy does not work, and one reason may be because the tumor microenvironment tends to be low on glucose and oxygen, slowing the ability of the cancer-killing immune cells to attack. A laboratory study by Scharping et al (2017) in mice with tumors found that metformin treatment alongside a checkpoint inhibitor was able to improve anti-tumor activity of the immunotherapy. The researchers believe this was because metformin helped to block tumor oxygen consumption and increase oxygen levels in the microenvironment, meaning more oxygen and energy was available for cancer-killing immune cells to do their job, once primed by the immunotherapy (Scharping et al., 2017).
A retrospective study of patients with malignant melanoma who were treated with immune checkpoint inhibitors (i.e. ipilimumab, nivolumab, and/or pembrolizumab), also found a trend (although not statistically significant) towards better treatment response rates and longer survival times in patients who were also taking metformin (Afzal et al., 2018).
Furthermore, in a different retrospective study in patients with advanced non-small cell lung cancer who were treated with nivolumab, statin use was associated with better and longer duration of treatment response (Omori et al., 2019).
Scientists have also suggested that ‘metabolic optimization’ of the tumor microenvironment might help to improve the effectiveness of a type of immunotherapy CAR-T therapy. CAR-T immunotherapy involves removing some of a patient’s own immune cells and ‘training’ them in a lab to detect and target the patient’s tumor. Some papers report that making the tumor microenvironment metabolically favorable for these reinvigorated immune cells may help them to sustain enough energy to effectively attack the tumor, once infused back into the patient (Li et al., 2019b; Xu et al., 2019).
Doxycycline and MMPs
Doxycycline may help to make cancer cells more ‘visible’ to immunotherapies. A preclinical cell study has reported that co-administration of doxycycline was able to improve the effectiveness of an experimental immune therapy and also an experimental cancer vaccine therapy, possibly in part through the antibiotic’s well-established modulation of enzymes called MMPs (Tang et al., 2013). MMP enzymes can help the cancer cell to ‘hide’ from the immune system by removing tell-tale immune-signaling molecules often expressed on the cancer cell surface. The researchers suggest that as doxycycline can inhibit MMP activity, the antibiotic may work to stop MMPs from removing these molecular signals, so helping the immune system better detect and target the cancer cell.
Preclinical and lab studies have suggested that some of the medications used in the COC Protocol may help the activity of monoclonal antibody treatments (Patel et al., 2015).
For example, patients with metastatic colorectal cancer with KRAS mutations are usually resistant to treatment with the monoclonal antibody cetuximab. However, a laboratory study has shown that the co-administration of a statin alongside cetuximab was able to reduce tumor growth of KRAS mutant tumors in mice, compared to cetuximab alone (Lee et al., 2011). In addition, encouraging responses were also noted in a follow-up uncontrolled clinical trial where patients with KRAS-mutant colorectal cancer who were no longer responding to conventional chemotherapy were treated with a combinatorial regime of simvastatin, cetuximab, and irinotecan (Lee et al., 2014).
A phase 2 trial in patients with HER2 positive breast cancer also found encouraging (though non-statistically significant) results with a paclitaxel/trastuzumab plus metformin regimen. Complete response to treatment was noted in 65.5% of patients in the plus metformin group compared to 58.6% patients in the non-metformin group (Martin-Castillo et al., 2018).
Of note, a 2008 lab study has suggested that statins might interfere with the monoclonal antibody rituximab’s ability to kill B cell lymphoma (Winiarska et al., 2008). However, more recent observational studies investigating statin use in patients with diffuse large B-cell lymphoma have found no suggestion of statin-induced impairment in rituximab effectiveness (Ennishi et al., 2010; Koo et al., 2011).
Hormone therapies are now regularly used to treat hormonal dependent cancers such as prostate cancer, breast cancer, and some gynecological cancers. Lab studies suggest COC medications can help to target cancer cells resistant to these treatments.
Tamoxifen is a hormone therapy widely used to treat hormone-dependent breast cancer. However, some patients can have reduced responses or resistance to tamoxifen. Cell studies suggest that metformin can help block activities that are associated with the development of metastases (i.e. migration and invasion) in tamoxifen-resistant breast cancer cells (Jang et al., 2014).
A different cell study found that when metformin was combined with tamoxifen, metformin helped to enhance the anticancer activity of tamoxifen at the cellular level, and the concentration of tamoxifen needed to block breast cancer cell growth in the lab was much reduced. Further studies in mice also showed that this combination of drugs ‘significantly inhibited tumor growth’ (Ma et al., 2014). In endometrial cancer, a lab study reported that metformin was able to target and reduce the growth of endometrial cancer cells resistant to treatment with progesterone (Zhuo et al., 2016).
Metformin and endometrial cancer
In an interesting Phase 2 study from 2016, patients with atypical endometrial hyperplasia or endometrial cancer took metformin alongside standard fertility-sparing hormone-based therapy. Metformin was then continued after the hormone-based therapy had finished until the patient had conceived or disease had relapsed. Just 10% of patients relapsed during the follow-up time (average 3 years), compared to an expected 26-47% relapse rate found in other studies where patients had only hormone-based therapy. The authors suggest that metformin helped to inhibit endometrial cancer recurrence following successful hormone-based treatment (Mitsuhashi et al., 2016), and that this combination for treatment of endometrial cancer requires further study.
Enzalutamide and abiraterone
Enzalutamide and abiraterone are hormone therapies used to treat advanced prostate cancer. Initial results from a small early-stage trial in patients with advanced prostate cancer who took metformin in combination with enzalutamide are encouraging. A recent update from the trial suggests the treatment was well tolerated in patients and may have clinical activity. However, further updates based on a more complete dataset are still required to help to clarify these findings (Parikh et al., 2019). A small trial which investigated the addition of metformin alongside abiraterone in men with advanced prostate cancer did not find any clinical benefit (Mark et al., 2019). Further trials are ongoing
A number of observational studies report potentially beneficial anticancer effects when patients take statins alongside these treatments. For example, a study of 598 patients who had been treated with abiraterone or enzalutamide for metastatic castrate-resistant prostate cancer after previously progressing on docetaxel found that average overall survival was increased in those who had received statins during treatment (20.8 months), compared to those who had not (12.9 months). Statin therapy in this study was associated with a 53% reduction in overall risk of death, and a 63% increased chance of a PSA decline of 30% or more in the first 12 weeks of treatment (Gordon et al., 2018).
A different study which reviewed the medical records of 187 patients with advanced prostate cancer who were treated with abiraterone also found statin use was associated with better overall survival. A greater proportion of patients in this study who were on statins also had PSA levels reduced >50% within 12 weeks (72.1% of statin users vs. 38.5% of non-users). And a meta-analysis which grouped and analyzed the results of 9 separate studies found that statin use was associated with a lower risk of death by any cause and death by cancer during the study period in patients with advanced prostate cancer who were treated with abiraterone (Yang et al., 2020).
One interesting case study documents a 62-year-old man with advanced prostate cancer who experienced a complete response to abiraterone. The researchers note that the patient had started taking a statin for high blood cholesterol at around the same time as abiraterone, and query whether this might have influenced the excellent treatment response (Yanai et al., 2019).
A cell study investigating the growth suppressing effects of statins on prostate cancer cells helps support these findings, reporting that statins enhanced growth suppression of prostate cancer cells ‘with added effects’ by abiraterone (Miller et al., 2017).
EGFR-TKIs (i.e., erlotinib and gefitinib) are often initially effective, but eventual development of treatment resistance is common. Several studies show that statins and metformin may help sensitize cancer cells to EGFR-TKI treatment and overcome resistance- at least for a period of time.
A randomized controlled Phase 2 study in 116 patients with advanced EGFR-mutated lung adenocarcinoma who took metformin alongside EGFR-TKIs compared to TKIs alone found that those who took metformin had longer progression-free survival (14 months vs 10 months), longer overall survival (27.2 months vs 19.0 months), and higher rates of response to treatment (objective response rate 67.4% vs 47.5%)(Arrieta Rodriguez et al., 2018). Similarly, a retrospective study which analyzed cancer outcomes for diabetic lung cancer patients treated with EGFR-TKIs found that metformin use was associated with longer survival and longer progression-free survival following TKI treatment (Hung et al., 2018). Lab studies have also shown that metformin can work with EGFR-TKI erlotinib to block basal breast cancer cell growth (Lau et al., 2014).
Beneficial effects of statins in combination with TKIs have also been demonstrated. Lab cell studies have found that statins (including atorvastatin) may help to overcome EGFR-TKI resistance in non-small cell lung cancer cells (Chen et al., 2013; Hwang et al., 2014; Park et al., 2010), and can enhance EGFR-TKI activity in glioblastoma cells (Cemeus et al., 2008).
An observational study which analyzed data from patients with KRAS-mutant lung cancer treated with EGFR-TKIs found that patients who were also taking a statin tended to have a longer time before disease progression and longer overall survival time (though overall survival difference was not statistically significant between the two groups) (Fiala et al., 2015). Encouraging results were also noted in a small randomized clinical trial in patients with non-small cell lung cancer, where subgroup analysis found that patients with wild-type EGFR non-adenocarcinomas might benefit from statin use alongside EGFR-TKI therapy (Han et al., 2011).
Bevacizumab (Avastin) is a targeted therapy which works to block the growth of tumor blood vessels. A study published in 2008 describes a case of a patient with the rare cancer rhabdomyosarcoma which was not responding to chemotherapy. Based on available evidence the doctors decided to try radiotherapy plus bevacizumab and statins. The patient’s tumor ‘responded clearly’, and curative surgery was performed (Lindén et al., 2008).
In a separate study, patients with non-small cell lung cancer were treated with bevacizumab plus chemotherapy with or without metformin. The trial was stopped early, but there was a clear trend for improved survival and length of time before disease progressed in patients who also took metformin, compared to expected values (Marrone et al., 2018). The authors state ‘[to our knowledge] this is the first trial in nondiabetic advanced non-small cell lung cancer patients to show a significant change in outcome with the addition of metformin to standard first-line chemotherapy’.
A study investigating the anticancer effects of metformin in lymphoma found that inducing metabolic stress in lymphoma cells by applying metformin alongside newer targeted therapies, such as bcl-2 inhibitors (venetoclax) or CDK9 inhibitors, significantly lowered the concentration of the targeted therapies needed to kill the cancer cells (Chukkapalli et al., 2018).
Lee et al (2018) also provides important evidence that statins can help to enhance the activity of bcl‑2 inhibitors, which are often used to treat blood cancers. The researchers found that statins helped to ‘prime’ the cancer cells to undergo pre-programmed death (apoptosis) in the presence of the bcl-2 inhibitor. They were able to show that bcl-2 inhibitors and statins can together have anticancer activity in several different cell models of leukemia and lymphoma and appeared to reduce lymphoma burden in a mouse model of the disease. In addition, the researchers retrospectively analyzed treatment responses rates for patients with chronic lymphocytic leukemia who had been treated with venetoclax in earlier clinical trials, and noted that patients taking statins during the trial were more likely to achieve complete response with venetoclax (26.7% with statins versus 15.2% without statins)(Lee et al., 2018).
A lab study tested the effectiveness of metformin and the MEK inhibitor trametinib on 16 different NRAS mutant cancer cell lines (including melanoma cells, melanoma cells with acquired trametinib resistance, lung cancer and neuroblastoma cells). The study found that this dual therapy was able reduce viability of cancer cells grown in dishes, and also tumors grown in animal models (Vujic et al., 2015).
Similarly, metformin increased the activity of MEK inhibitor binimetinib in 2D and 3D models of human metastatic melanoma cells (Ryabaya et al., 2019). An interesting study found that mebendazole may also work alongside trametinib to slow the growth of some types of NRAS and BRAF-mutant melanomas in cell studies and mouse tumor models (Simbulan-Rosenthal et al., 2017).
PARP inhibitors block poly ADP ribose polymerase, an enzyme involved in cancer cell DNA repair.
A 2019 lab study suggests that metformin can help reduce cell changes which contribute to development of resistance to PARP inhibitors in triple-negative breast cancer cells (Han et al., 2019). The study found that metformin could make breast cancer cells more sensitive to PARP inhibitors and more vulnerable to the effects of cytotoxic immunoregulatory T cells. The authors suggest ‘a combination of metformin and PARP inhibitors may be a promising therapeutic strategy to increase the efficacy of PARP inhibitors and tumor sensitivity to immunotherapy’.
A different cell study found that metformin can enhance the activity of the PARP inhibitor olaparib in BRCA positive ovarian cancer cells grown in the lab, and in mice with BRCA positive ovarian cancer tumors (Hijaz et al., 2016). In this study, combined application of both olaparib and metformin inhibited cancer cell growth to a greater extent than using either treatment alone.
Cell work also shows that doxycycline and other tetracyclines are also quite potent inhibitors of the PARP enzyme (Szabo et al., 2006). These and other mechanisms of action have led some researchers to suggest that doxycycline may have a role as an effective enhancer of biological anticancer therapies (Tang et al., 2013).
CDK 4/6 inhibitors are targeted blockers of CDK 4 and CDK 6 enzymes, which are important in ensuring cell division goes smoothly.
A study in hepatocellular carcinoma (liver cancer) cells grown in the lab found that CDK 4/6 inhibitors may partially work through the AMPK signaling pathway in cancer cells. Metformin is also known to modulate this pathway, and co-application of metformin with CDK 4/6 inhibitor ribociclib induced cell death (when application of either drug alone did not) (Hsieh et al., 2017). A recent study of the molecular drivers of liver cancer in mice also suggested a potential dual role for metformin and CDK 4/6 inhibitors in the therapeutic targeting of obesity/diabetes related liver tumors (Luo et al., 2020). Metformin was reported in this study to impact activity of cyclin D1, a molecular associate of CDK 4/6 enzymes.
Other studies have also found a potential therapeutic role regarding metformin’s ability to impact cyclin D1 in prostate cancer cells (Sahra et al., 2008), and esophageal squamous cell carcinoma. In this last study, co-application of metformin with another cancer cell metabolism disruptor (an experimental compound which blocked the metabolic enzyme glutaminase 1), was able to initiate cancer cell death in CDK 4/6 inhibitor resistant cells, showing promise for cancers which have become resistant to these therapies (Qie et al., 2019).
Of note, our oncologists are aware of literature reports of a possible moderate drug-drug interaction effect of statins and the CDK 4/6 inhibitor palbociclib (Li et al., 2019a; Nelson et al., 2017; Nersesjan et al., 2019). Although reportedly rare, this potential interaction nevertheless remains a risk factor, which our clinicians monitor for closely and manage accordingly. These findings again underline the importance of the long-term medical oversight and guidance provided for all patients who attend Care Oncology Clinic.
Cell studies suggest metformin can also enhance the anticancer activity of HDAC inhibitors in osteosarcoma cells (Duo et al., 2013), and the proteasome inhibitor bortezomib in patient-derived myeloma cells (Jagannathan et al., 2015).
The mechanism of action of metformin has also been suggested to combine well with the mTOR inhibitor temsirolimus, particularly for ovarian and breast cancers (Santos Guimaraes et al., 2017). Very preliminary data from a small Phase 1 trial helps to back this up (Khawaja et al., 2016).
Immunotherapy (i.e., treatments such as monoclonal antibodies, targeted therapies, oncolytic viruses, T cell therapy and cancer vaccines, alongside the PD1 and PDL1 checkpoint inhibitors) is a suite of novel therapeutic interventions with constantly evolving data. Immunotherapy use is growing fast, for example, these therapies are increasingly prescribed as a first-line treatment and are administered in a greater number of cancer types. Use of double immunotherapy combinations, or immune checkpoint inhibitors combined with conventional systemic anticancer therapies is also becoming more common.
In light of this rapid expansion in use of immunotherapies, studies are now investigating the potential impact of antibiotic-induced alteration of the gut microbiome on immunotherapies such as checkpoint inhibitors and CTLA-4 inhibitors (Kapoor et al., 2020).
Indeed, a 2019 paper by Pinato et al. discussed introducing a higher threshold for antibiotic prescribing for cancer patients due to receive immunotherapy (Pinato et al., 2019). While this research paper has author-acknowledged limitations (including the small number of patients, lack of direct observations of changes to the gut microbiome, potential impact of any other health conditions the patients may have had), this topic will also certainly benefit from further research.
In line with Care Oncology’s cautious approach, and in acknowledgement of this rapidly evolving field of research, our clinicians will carefully assess each patient who is on immunotherapy or likely to start immunotherapy in future. Although bacteriostatic antibiotics such as doxycycline (which is used in the COC Protocol) are not negatively implicated in current research, in certain cases, a decision may be taken for doxycycline to be omitted or paused for a period of time.
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