NSAID's and cancer (Colon and melanoma specifically!) ~

Much has been written in the literature regarding NSAID use and melanoma. NSAID's are drugs like aspirin, ibuprofen, naproxen, and lots of prescription ones, that block COX enzymes.  Enzymes that produce prostaglandins which lead to inflammation, pain and fever when left to do their own thing.  By blocking the enzyme, NSAID's reduce the prostaglandins and the unpleasantness they cause.  I first reported on them in 2012!  Here is a break down of how they might work in melanoma world from 2015:  An aspirin a day...keeps melanoma at bay....and makes immunotherapy work better!!!! 
Here are a zillion additional reports:  NSAID's - do they help or not? 
Basically, the data (and reports) cover:
"YES!!!  NSAID's make immunotherapy work better!"   "NSAID's increase survival in melanoma patients."  "No, NSAID's make no difference."

Though these drugs are not to be trifled with despite being accessible over the counter, most data says at worst they "do no harm".  Given the aches and pains immunotherapy causes, I've long said you would be hard pressed to find a patient on immunotherapy who did NOT partake in the use of NSAID's!!  I know I certainly took my share of advil during my treatment!!!  Now, there's this:

The Impact of Nonsteroidal Anti-Inflammatory Drugs, Beta Blockers, and Metformin on the Efficacy of Anti-PD-1 Therapy in Advanced Melanoma.  Wang, McQuade, Rai, et al.  Oncologist.  2019 Nov 29.

Anti-programmed cell death protein-1 (anti-PD-1) therapy has greatly improved outcomes of patients with melanoma; however, many fail to respond. Although preclinical studies suggest a potentially synergistic relationship with anti-PD-1 therapy and certain concurrent medications, their clinical role remains unclear. Here, we retrospectively evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and other drugs in 330 patients with melanoma treated with anti-PD-1 therapy from four academic centers. In the cohort, 37% of patients used NSAIDs including aspirin (acetylsalicylic acid; ASA; 47%), cyclooxygenase (COX)-2 inhibitors (2%), and non-ASA/nonselective COX inhibitor NSAIDs (59%). The objective response rates (ORRs) were similar in patients with NSAID (43.4%) and no NSAID (41.3%) use with no significant difference in overall suvival (OS). There was a trend toward improved progression-free survival (PFS) in patients who took NSAIDs (median PFS: 8.5 vs. 5.2 months). Most patients (71.3%) took NSAIDs once daily or as needed. Multivariate analysis did not reveal an association with NSAID use with ORR, PFS, or OS. Concurrent use of metformin or beta blockers did not affect ORR, PFS, or OS. Our study found no conclusive association of concurrent NSAID or other medication use with improved outcomes in patients with melanoma treated with anti-PD-1 therapy. Larger and more systematic analysis is required to confirm these findings.

Given my current condition, it is pertinent that my 2015 report started with this quote:
 "NSAID's, including aspirin, decrease the incidence and mortality from colon cancer in humans by 45% to 50%."  DuBois, Cancer Research, 56(4), 1996.

Now, there's this - The Association between NSAID use and Colorectal Cancer Mortality: Results from the Women's Health Initiative

Which notes:  "Randomized trial evidence demonstrates that non-steroidal anti-inflammatory drug (NSAID) use, particularly long-term use, reduces the incidence of colorectal neoplasia. Recent data also suggests an inverse association between NSAID use and death due to colorectal cancer (CRC). We examined the association between NSAID use and CRC mortality among 160,143 post-menopausal women enrolled in the Women's Health Initiative. Women provided details on medication use at baseline and three years after enrollment. Overall, NSAID use at baseline was not associated with CRC mortality. However, women who reported NSAID use at both baseline and year-three experienced reductions in CRC mortality compared to non-users.  Results suggest that NSAID use is associated with lower CRC mortality among post-menopausal women who use these medications more consistently over time. Our results support prolonged NSAID use in post-menopausal women for the prevention of poor CRC outcomes."

I have discussed all of this with my various docs.  They didn't have too much to say or contribute on the subject one way or another.  However, I was given their blessing to start an aspirin regimen of one baby aspirin (81mg) per day.  So, I did!  For what it's worth! - c

Sooo....advil works for SOME melanoma patients?????

I first reported on the supposed benefits of NSAID's ability to decrease cancer risk in 2012:  NSAID's and risk of skin cancer

Then last year (with much pandemonium in various news outlets this year) it was published that NSAID's reduced the bad boys - myeloid derived suppressor cells (MDSCs) and made anti-PD1 work better. 

Here's one post from 2015:  An Aspirin a day keeps melanoma at bay

And another from 2016:  Celecoxib: The stuff that's in NSAID's work synergistically with anti-PD1

Then at ASCO, they poured cold water over the whole thing.  See the last article in this post:  ASCO 2016: NSAID's many not aide response to anti-PD1 after all! 

But now, there's this: 

Differential expression of cyclooxygenase-2 in metastatic melanoma affects progression free survival.  Panza, De Cicco, Ercolano, et al.  Oncotarget. 2016 Aug 1.

The possible correlation between cyclooxygenase-2 (COX-2) expression and disease progression in melanoma is still a matter of debate. Analysis of COX-2 expression in 45 lymph node melanoma metastases demonstrates a significant correlation between the percent of expression and progression free survival (PFS). A positive COX-2 expression ≥10% (COX-2high), as opposite to a positive expression ≤9% (COX-2low), translated into a striking significant reduction of PFS of about 3 years. The reduction in PFS correlated neither with BRAFV600E nor with NRASQ61 expression in the analyzed samples. This concept was reinforced by the finding that tumour development in COX-2-/- mice was almost blunted. Similarly, inhibition of COX-2 protein expression in human melanoma cell lines, by using siRNAs technology as well as selective inhibition of COX-2 activity by celecoxib, reduced cellular proliferation and invasiveness. In conclusion we show that COX-2high is a negative prognostic factor in metastatic melanoma. Our study also clarifies that the uncertainty about the role of COX-2 in metastatic malignant melanoma, found in the current relevant literature, is probably due to the fact that a threshold in COX-2 expression has to be reached in order to impact on cancer malignancy. Our findings suggest that COX-2 expression may become an useful diagnostic tool in defining melanoma malignancy as well as argue for a possible therapeutic use of NSAID as add on therapy in selected cases.

For what it's worth!!! - c

An aspirin a day...keeps melanoma at bay....and makes immunotherapy work better!!!!

We have long known that NSAID's (nonsteroidal anti-inflammatory drugs) decrease the risk of many cancers.  For instance:

"NSAID's, including aspirin, decrease the incidence and mortality from colon cancer in humans by 45% to 50%."  DuBois, Cancer Research, 56(4), 1996.

That's old, y'all!!!  More recently, (well, in 2012) researchers in Denmark looked at the medical records of 18,000 people from 1991-2009 and found that: "people who had taken aspirin, ibuprofen and related painkillers -- especially at high doses and for years at a time -- were less likely to get skin cancer, compared to those who rarely used those medications.  The findings add to growing evidence that long-term use of the medications, known as nonsteroidal anti-inflammatory drugs, or NSAIDs, may help protect people against skin cancers, including melanoma, the deadliest type."  Common painkillers tied to lower skin cancer risk

And now....there's this from Zelenay et al., Cell, September 2015:  Cyclooxyenase-dependent tumor growth through evasion of immunity

Which sounds very fancy....but here's the deal:   To back up a step -  NSAIDs block an enzyme, cyclooxygenase (also called: COX1 and COX2).  Blocking those enzymes, blocks the production of prostaglandins.  Soooo..... These researchers used genetically modified mice to research the role of prostaglandins in blocking immune rejection of tumors.  Aspirin and similar NSAIDs stop the production of prostaglandins, thereby allowing immune cells to kill tumors more easily and enhancing the checkpoint inhibitors like anti-PD1 (nivo/opdivo and pembro/keytruda), anti-PDL1, and anti-CTLA4 (ipililmumab).  They note:

• Prostaglandins in tumors interferes with immune cell function.
• Blocking cyclooxygenase in tumors restores immune cell function.
• The cyclooxygenase blockers (NSAIDs) increase the action of checkpoint inhibitors.
• This mechanism is shared by mouse and human tumor systems.

My thoughts:  While you can find conflicting reports regarding effects of NSAIDs and this latest study was done with real ratties (ie the 4 legged kind!!), the benefit of COX inhibitors in the form of NSAIDs sounds like a pretty common sense, low risk, and reliable finding to aid patients' results from immunotherapy.  I am certain that my study did NOT control for NSAID use, but I imagine it is a pretty rare anti-PD1 patient who does not utilize ibuprofen to deal with arthralagias and other aches and pains the therapy produces!!  I know I certainly lived on advil and benadryl to deal with my rashes and beat up joints.  Of course, the next step will be an examination of the application in human ratties....  So, time will tell.  But, I think I'll keep taking my ibuprofen....unless Bentie makes me switch to aspirin!!!

Love - c

COX-2 expression correlates with PD-L1 expression on melanoma cells - or....how NSAID's like aspirin and advil might help melanoma patients????

COX-2 expression in melanoma cells is what has given the hope (??? data) that the use of NSAID's (advil, aspirin, etc) might enhance the response from immunotherapy in melanoma patients as noted in this post (with links to others within):  Sooo....advil works for SOME melanoma patients?????

COX-2 expression positively correlates with PD-L1 expression in human melanoma cells. Botti, Fratangelo, Cerrone, et al. J Transl Med. 2017 Feb 23.

The resistance to PD-1/PD-L1 inhibitors for the treatment of melanoma have prompted investigators to implement novel clinical trials which combine immunotherapy with different treatment modalities. Moreover is also important to investigate the mechanisms which regulate the dynamic expression of PD-L1 on tumor cells and PD-1 on T cells in order to identify predictive biomarkers of response. COX-2 is currently investigated as a major player of tumor progression in several type of malignancies including melanoma. In the present study we investigated the potential relationship between COX-2 and PD-L1 expression in melanoma.

Tumor samples obtained from primary melanoma lesions and not matched lymph node metastases were analyzed for both PD-L1 and COX-2 expression by IHC analysis. Status of BRAF and NRAS mutations was analyzed by sequencing and PCR. Co-localization of PD-L1 and COX-2 expression was analyzed by double fluorescence staining. Lastly the BRAF^V600E A375 and NRAS^Q61R SK-MEL-2 melanoma cell lines were used to evaluate the effect of COX-2 inhibition by celecoxib on expression of PD-L1 in vitro.

BRAF^V600E/V600K and NRAS^Q61R/Q61L were detected in 57.8 and 8.9% of the metastatic lesions, and in 65.9 and 6.8% of the primary tumors, respectively. PD-L1 and COX-2 expression were heterogeneously expressed in both primary melanoma lesions and not matched lymph node metastases. A significantly lower number of PD-L1 negative lesions was found in primary tumors as compared to not matched metastatic lesions. COX-2 expression significantly correlated with PD-L1 expression in both primary and not matched metastatic lesions. Furthermore, in melanoma tumors, cancer cells expressing a higher levels of COX-2 also co-expressed a higher level of PD-L1. Lastly, inhibition of COX-2 activity by celecoxib down-regulated the expression of PD-L1 in both BRAF^V600E A375 and NRAS^Q61R SK-MEL-2 melanoma cell lines.  

COX-2 expression correlates with and modulates PD-L1 expression in melanoma cells. These findings have clinical relevance since they provide a rationale to implement novel clinical trials to test COX-2 inhibition as a potential treatment to prevent melanoma progression and immune evasion as well as to enhance the anti-tumor activity of PD-1/PD-L1 based immunotherapy for the treatment of melanoma patients with or without BRAF/NRAS mutations.

Breaking it down:  This report supports the notion that there is a relationship between COX-2 and PD-L1 expression in melanoma. Therefore, if we could block COX-2 we would reduce PD-L1 expression in melanoma cells and make anti-PD-1 drugs more effective. That's the theory anyway!!   - c

Trial to test aspirin's ability to prevent cancer relapse...

You may remember this recent post:  An aspirin a day keeps melanoma at bay and makes immunotherapy work better!

Basically, we have known for a long time that NSAID's (and aspirin in particular) helps prevent a variety of cancers.  Further, in the study included in my post, genetically engineered mice attained greater benefit from immunotherapy when given NSAID's along side!

Now, there's this:

"Cancer Research UK and the British National Institute for Health Research are launching the Add-Aspirin Phase III trial with plans to recruit 11,000 patients who have been treated or are being treated for bowel, breast, esophageal, prostate or stomach cancer.  The study could run for as long as 12 years as researchers monitor the effects of daily aspirin use for five years on cancer."  Here's the link:  Large trial to test aspirins ability to prevent cancer relapse

"Researchers plan to split participants into three groups: one-third of the participants will receive a 300 mg aspirin tablet each day; one-third will be given 100 mg tablets; and the rest will receive a placebo. Doctors and patients will not be told which of the treatments the participants are given.  The participants will be closely monitored for any effects on their health, most significantly whether their cancer has come back."

While melanoma is not included here...I think this could provide a lot of good information for all of us.  Good luck, ratties!!!! - c

Aspirin, NSAID's, and melanoma

I first posted on this bunch of mess in 2012!!!!  (I'm getting old and in melanoma land ~ or any other land, really ~ that is AWESOME!!!!)   Here's a link to a complete re-cap:  Sooo....advil works for SOME melanoma patients?????  As you can see from these posts:  Aspirin and other NSAID's decrease rates of melanoma!!  Well, maybe!!!  Advil and such make immunotherapy work better in treating melanoma.  Oh, perhaps not....or just for certain peeps! 
Hmmmm......  Now, there's this....

Post-diagnosis aspirin use and overall survival in patients with melanoma.  Wallace, Li, et al.  J Am Acad Dermatol. 2018 Jan 6.   

Mouse studies show that tumor-derived prostaglandins and platelets promote melanoma progression and immune-evasion. [To] Determine if aspirin confers longer survival in patients with melanoma - A retrospective cohort study of 1,522 patients at Indiana University Health (IUH) diagnosed with melanoma between 2000 and 2014 and followed up through September, 2016.

Aspirin use was associated with longer overall survival in univariate analysis and after controlling for age, sex, stage, and treatment modalities. Aspirin use was not associated with survival in patients with in situ and stage I melanoma, but was associated with better survival in stages II and III. No statistical significance was observed in stage IV patients. In turn, patients using aspirin before diagnosis were less likely to be diagnosed in stages III or IV disease. Observational study. Aspirin could provide a survival advantage in melanoma. Clinical trials investigating the therapeutic potential of aspirin are warranted.

In this study, researchers in Indiana reviewed the files of 1,522 melanoma patients diagnosed at their university between 2000 and 2014 and followed them through September of 2016.  Aspirin use was NOT associated with survival in patients with Stage I and in situ melanoma.  However, aspirin WAS associated with better survival for Stage II and III patients, while no statistical difference was found in Stage IV patients.  However, patients who used aspirin BEFORE they were diagnosed were found less like to "be diagnosed in Stages III or IV disease". 

Hmmm.....You gotta love it when a new study only adds more confusion (or is that confirmation?????) to a yes/no situation!!!  Oh, well.  Melanoma provides no easy answers.  Low dose aspirin daily rarely hurts and helps some in a variety of ways.  Not something I've every partaken in....though advil has been an almost daily drug since taking anti-PD-1 for 2 1/2 years.  I think you'd be hard pressed to find immunotherapy patients who haven't been simultaneously "contaminated with" NSAID use, given the aches and pains the treatment produces.  Anyhow....still not sure what all this really means...if anything.  Be sure to talk to your doc about all your over the counter medicines and before starting a legit ASA regimen!  For what it's worth..... - c

Old Stuff from the newest ASCO - NLR association with response and survival in advanced melanoma, SRS with targeted or immunotherapy for melanoma brain mets, COX2 inhibitors (NSAID's) and improved response to anti-PD-1 therapy in melanoma

Yeah.  Most of this jazz, is NOT news.

I have been yelling about NLR and its relationship to response in melanoma patients FOREVER!!!  Here are only a million prior reports:  Better melanoma outcomes with a lower NLR, neutrophil-to-lymphocyte ratio! (Again...) Now, this:

Association of baseline neutrophil-to-lymphocyte ratio (NLR) with response and survival in advanced melanoma (MEL) receiving PD-1 inhibitors.  2019 ASCO.  Hemadri, Lin, Lin, et al.   J Clin Oncol 37, 2019 (suppl; abstr 9571)

Background: Inflammation is an adverse prognostic factor in cancer. Neutrophil-to-lymphocyte ratio (NLR) is an easily derived biomarker of systemic inflammation. Several studies have demonstrated that elevated NLR is linked with adverse prognosis in patients (pts) receiving immunotherapy including PD-1 inhibitors. To evaluate the prognostic utility of NLR, we performed a retrospective evaluation of NLR and other covariates in stage IV cutaneous MEL. Methods: Stage IV cutaneous MEL pts who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Baseline NLR was defined based on values at the first treatment date. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mos). Results: 172 pts with advanced MEL were evaluated. Elevated NLR was associated with poorer PFS and OS and ORR at all cutoffs (NLR greater than/= to 2 to NLR greater than/= to 5) with NLR greater than/= to 5 having the greatest discriminative value. ORR steadily declined with increasing NLR: NLR greater than/= to 1 (ORR 64%), NLR greater than/ = to 2 (ORR 61%), NLR greater than/= to 3 (ORR 52%), NLR greater than/= to 4 (ORR 43%), NLR greater than/ = to 5 (ORR 43%). Elevated NLR was associated with poorer PFS (median 21.5 mos vs. 5.2 mos) and OS (median 35.4 mos vs. 10.6 mos). In a multivariate model, elevated NLR  was independently associated with poorer OS/PFS separate from ulceration, performance status and elevated LDH. There was no evidence of an age-related increase or decrease in NLR. Conclusions: Baseline NLR was independently associated with response, PFS and OS in the largest retrospective series of advanced MEL pts treated with PD-1 blockade. NLR independent of other factors predicted poorer PFS and OS at NLR cutoffs (NLR greater than/= to 3 to NLR greater than/= to 5), although NLR greater than/+ to 5 segregated pts best. NLR is an inexpensive and easily obtained real-world biomarker that has a high value in predicting outcomes to PD-1 blockade.

Once again, elevated NLR was associated with worse outcomes across the board, including PFS, OS, and ORR - in melanoma patients treated with immunotherapy - even when separated from ulceration, patient status, and elevated LDH.  This is a cheap and easy test that might aid patients and docs in their selection of treatment options!  

When dealing with brain mets, we have learned that when systemic therapy (targeted or immunotherapy) is combined with radiation (SRS) the response is better than with either treatment option alone.  Here are a zillion reports: Radiation combined with systemic therapy in melanoma treatment - 2015 forward  Now, this:

First-line stereotactic radiosurgery combined with systemic targeted and immune checkpoint inhibitor therapy in melanoma patients with newly diagnosed brain metastases.  2019 ASCO.  Heumann, Wu, Ye, ..., Weber, Pavlick, et al.  J Clin Oncol 37, 2019 (suppl; abstr e13577)

Background: Of solid tumors, melanoma has the highest propensity for central nervous system spread with historic median survivals of 5-8 months following brain metastasis diagnosis. We evaluated the impact of systemic BRAF targeted and immune checkpoint inhibitor (ICI) therapies on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases (MBM) and assessed patient treatment burden associated with prolonged survival. Methods: We retrospectively reviewed the demographics, disease characteristics, therapeutic regimens, overall survival, and first-year cumulative incidence of comorbid disease for patients with de novo MBM treated between 2013 and 2017 at a major melanoma referral center. Results: Among 123 newly diagnosed MBM patients:  65% were male, 24% were 50 years old or less, 50% were BRAF mutated, 63% had multiple intracranial lesions at diagnosis. Locally, 73% received SRS as first-line treatment.Systemically, 73% received ICI, 46% received BRAF targeted therapy, and 12% received neither. With median follow up of 11 months (mo), total cohort median OS was 13.2 mo, 20.5 mo for BRAF mutated patients, 10.8 mo for BRAF wild-type patients. Median OS for first-line SRS was 31.0 mo (47% 3-year OS) when combined with both ICI and BRAF targeted therapy, 17.5 mo (31% 3-year OS) when combined with ICI monotherapy, and 6.1 mo (22% 3-yr OS) with neither systemic therapy. SRS and BRAF targeted therapy were associated with improved OS. BRAF status, ICI therapy, intratumoral hemorrhage were not significant prognosticators for OS.At one-year follow-up, comorbid conditions with the greatest cumulative incidence were fatigue, nausea, intracranial hemorrhage, deep vein thrombosis, major depressive disorder, and pneumonia. Patients averaged one inpatient visit every 4.5 mo (1 week average length of stay), and 2 advanced imaging studies (MR/CT/PET-CT) per month following MBM diagnosis. Conclusions: In one of the largest reported MBM series, survival has improved markedly for patients receiving first-line brain radiosurgery combined with BRAF targeted therapies and immunotherapies. Simultaneously, longer life expectancy comes with increasing incidences of comorbid conditions reflecting an evolving complexity of and need for coordination of care for patients with MBM. 

Wait for it...  Folks with melanoma brain mets did better when they were treated with targeted therapy or immunotherapy combined with radiotherapy, than with either of the treatments as single agents!

COX inhibitors, your basic NSAID's ~ think aspirin or advil ~ have long been a topic of discussion as they relate to responses from immunotherapy.  In this post from 2015, An aspirin a day...keeps melanoma at bay....and makes immunotherapy work better!!!!, I noted, "...here's the deal:   To back up a step -  NSAIDs block an enzyme, cyclooxygenase (also called: COX1 and COX2).  Blocking those enzymes, blocks the production of prostaglandins.  Soooo..... These researchers used genetically modified mice to research the role of prostaglandins in blocking immune rejection of tumors.  Aspirin and similar NSAIDs stop the production of prostaglandins, thereby allowing immune cells to kill tumors more easily and enhancing the checkpoint inhibitors like anti-PD1 (nivo/opdivo and pembro/keytruda), anti-PDL1, and anti-CTLA4 (ipililmumab).  Researchers note:

• Prostaglandins in tumors interferes with immune cell function.
• Blocking cyclooxygenase in tumors restores immune cell function.
• The cyclooxygenase blockers (NSAIDs) increase the action of checkpoint inhibitors.
• This mechanism is shared by mouse and human tumor systems.

My thoughts:  While you can find conflicting reports regarding effects of NSAIDs and this latest study was done with real ratties (ie the 4 legged kind!!), the benefit of COX inhibitors in the form of NSAIDs sounds like a pretty common sense, low risk, and reliable finding to aid patients' results from immunotherapy.  I am certain that my study did NOT control for NSAID use, but I imagine it is a pretty rare anti-PD1 patient who does not utilize ibuprofen to deal with arthralagias and other aches and pains the therapy produces!!  I know I certainly lived on advil and benadryl to deal with my rashes and beat up joints.  Of course, the next step will be an examination of the application in human ratties....  So, time will tell.  But, I think I'll keep taking my ibuprofen....unless Bentie makes me switch to aspirin!!!"

Then there was some back and forth in this composite of many posts and articles in 2018:  Aspirin, NSAID's, and melanoma  Now, there's this:

Evaluating the role of the COX2/PGE2 pathway in anti-melanoma immunity.  2019 ASCO.  Ferreira, Krybaeva, et al.  J Clin Oncol 37, 2019 (suppl; abstr e14114)

Background: Checkpoint inhibitors such as anti-PD1 (aPD1) have revolutionized treatment of metastatic melanoma. However, a large subset of patients receiving such treatment fails to respond to aPD1 monotherapy due to mechanisms such as PD-L1 upregulation within the tumor and T cell exhaustion in the tumor microenvironment. The PGE2/COX2 signaling pathway is one of the pathways implicated in T cell exhaustion and PD1/PD-L1 upregulation and thus represents an attractive pharmacologic target to enhance effects of aPD1 therapy due to the availability and safety of inhibitors such as aspirin or NSAIDs. There is evidence that PGE2/COX2 pathway inhibitors act synergistically with aPD1 therapy in murine melanoma and breast cancer models. Here we aimed to further characterize this synergism using the YUMMER (Yale University Mouse Melanoma Exposed to Radiation) 1.7 model, an irradiated, syngeneic cell line originating from BrafV600E; Pten-/-; and Cdkn2a-/- genetically engineered mouse melanomas. YUMMER1.7 cells implanted into the flanks of C57BL6/j mice show reproducible but partial responses to intraperitoneal aPD1 therapy and thus serves as an ideal platform to study whether concurrent PGE2/COX2 pathway blockade may result in additive effects to aPD1 therapy. Methods: 6-7 week old male C57BL6/j mice (n = 20) were injected with 500K YUMMER1.7 cells and treated with aPD1 therapy alone starting on day 7 after tumor implantation (n = 10) or with aPD1 therapy starting on day 7 in addition to ibuprofen dissolved in drinking water at a concentration of 1 mg/mL started on the day of tumor implantation (n = 10). Using an average daily water consumption estimate of 6 mL/day, this translates to a human equivalent of roughly 1200 mg/day, a moderate dose of ibuprofen. Tumor growth was monitored and tracked to an endpoint of 1cm3. Results: Tumor volume at day 17 significantly differed between the two groups. Survival curves were significantly different between the two groups (p < 0.0001); all tumors treated with aPD1 alone grew to endpoint by day 32, while all tumors treated with aPD1 + ibuprofen regressed with 8 out of 10 showing complete regression by day 32. Conclusions: We have shown that ibuprofen strongly synergizes with aPD1 therapy in a murine model of melanoma, complementing existing evidence. This suggests that PGE2/COX2 inhibitors such as NSAIDs, which are over-the-counter agents with a well-studied safety profile, may serve as a promising means of enhancing the response to aPD1 therapies such as nivolumab in melanoma patients who initially fail aPD1 monotherapy.

Well, okie dokie then!  Not sure just taking anti-PD-1 with an aspirin is going to work for folks who failed anti-PD-1 in the first place, especially since I think it would be a hard task to find a melanoma peep on anti-PD-1 who hasn't had to dip into the NSAID bottle of choice in order to survive the assorted aches and pains that come with that therapy!  But what do I know?????

There is beauty still...

... even if we come through the storm looking something like a Dr. Seuss flower!  - c

Celecoxib (Stuff that's in NSAID's like ibuprofen and aspirin!!!) and anti-PD1 work synergistically

I put this post up a while ago: An aspirin a day keeps melanoma at bay and makes immunotherapy work better???   As I noted in that post....I figure all us immunotherapy peeps have pretty much been living on advil in order to deal with our arthralgias!!!  But, this was republished recently:

Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity.  Li, Fang, Zhang, et al.  Oncoimmunology. 2015 Aug 12;5(2):e1074374. eCollection 2016. 

Two major challenges facing cancer immunotherapy are the relatively low therapeutic efficacy and the potential side effects. New drug delivery system and efficient drug combination are required to overcome these challenges. We utilize an alginate hydrogel system to locally deliver 2 FDA-approved drugs, celecoxib and programmed death 1 (PD-1) monoclonal antibody (mAb), to treat tumor-bearing mice. In two cancer models, B16-F10 melanoma and 4T1 metastatic breast cancer, the alginate hydrogel delivery system significantly improves the antitumor activities of celecoxib (CXB), PD-1 mAb, or both combined. These effects are associated with the sustained high concentrations of the drugs in peripheral circulation and within tumor regions. Strikingly, the simultaneous dual local delivery of celecoxib and PD-1 from this hydrogel system synergistically enhanced the presence of CD4⁺inteferon (IFN)-γ⁺ and CD8⁺IFN-γ⁺ T cells within the tumor as well as in the immune system. These effects are accompanied with reduced CD4⁺FoxP3⁺ regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) in the tumor, reflecting a weakened immuosuppressive response. Furthermore, this combinatorial therapy increases the expression of two anti-angiogenic chemokines C-X-C motif ligand (CXCL) 9 and CXCL10, and suppresses the intratumoral production of interleukin (IL)-1, IL-6, and cycloxygenase-2 (COX2), suggesting a dampened pro-tumor angiogenic and inflammatory microenvironment. This alginate-hydrogel-mediated, combinatorial therapy of celecoxib and PD-1 mAb provides a potential valuable regimen for treating human cancer.

Hmmmm.... "reduced myeloid derived suppressor cells (MDSCs)"....  Now that could be something!!  Remember this?   Increased Myeloid Suppressor cells = not so good.

And for what it's worth....there was also this back in the day:  
Nonsteroidal anti-inflammatory drugs and the risk of skin cancer:  A population-based case-control study. Johannesdottir, Chang, Mehnert, et al.  Cancer, 2012, May 29.

Knowing that Nonsteroidal anti-inflammatory drugs (NSAIDS....like aspirin, ibuprofen, etc.) may prevent the development of cancer by inhibiting cyclooxygenase (COX) enzymes, these folks from Denmark looked at NSAID use and the risk of squamous cell carcinoma, basal cell carcinoma, and melanoma.  They looked at all cases of those diseases from 1991 through 2009 in northern Denmark. (Squamous = 1,974, basal = 13, 316, and melanoma = 3,242).  They matched 10 population controls (n=178,655) to each case by age, gender, and county of residence.  Use of NSAIDs was noted via a prescription data base.  FINDINGS:  After a great deal of incidence rate ratios and confidence interval statistical shenanigans....they determined that "NSAID ever use compared with nonuse was associated with a decreased risk of squamous cell and melanoma, especially for long-term use and high-intensity use.  NSAID use was not associated with a reduced risk of basal cell.  All estimates of reduced risk were driven primarily by the use of nonselective NSAIDs and older COX-2 inhibitors."

Just putting it out there.  Best - c

Everything cures/kills melanoma ~ one 'mo one....

If you look back on my post from July 20, 2013 you'll see a large collection of research articles enumerating studies that proved all sorts of things - coffee, cucumin (turmeric), cimetadine (tagamet...med to decrease stomach acid), doxycycline (an older antibiotic), NSAID's (like ibuprofen), and even shitake mushrooms - kill melanoma cells!!!  Well, here's another:  STRAWBERRY JUICE!

Antineoplastic activity of strawberry (Frafaria x ananassa Duch.) crude extracts on B16-F10 melanoma cells
By:  Forni, Braglia, Mulinacci, Urbani, et al.
Of the Department of Biology, University of Rome, via Mol Biosyst, 2013 Nov 4. [Epub]

So....these peeps extracted the juice from strawberries (anthocyanin-rich strawberry fruit crude extracts) and squirted it on some mouse melanoma cells they had scattered about in petri dishes and found.... {DRUMROLL>>>>>}.... "the strawberry extract produced a remarkable reduction of cell proliferation."

Thought you should know.  Now...go have a "fruit snack"!!!!

PS...Fred, Shane, and Rose should never have any worries having eaten more than their weight in fruit a zillion times over!!!  Remember Fred trying to get out of the grocery cart to get to the strawberries when he was a baby, Ruthie????

Wonder if it counts if you eat strawberry ice cream?  Hmmmmm... - c

EVERYTHING cures melanoma....so why do we have it??????

B saw the latest "coffee" data yesterday and it got me thinking about all the things that CURE melanoma!!!!  Now, mind you, I'm not claiming they do or they don't. The data is either too vague, too limited, or has so little to do with people that you can't tell.  AND....because there are no big bucks to be made as all of these things are pretty cheap, food, or over the counters...I don't see anybody forking over the money for study.  Oh well....for what it's worth....

COFFEE:  More than once daily...if you have the right genes, shows a "protective effect" for cutaneous melanoma.  Not sure exactly what that means, and not really clear if these genes might be the protection in and of themselves, without the addition of coffee.  Presumably they looked at that, but????

DOXYCYCLINE:  An older antibiotic, causes some nausea, but pretty good in treating acne, but...apparently...it kills and inhibits growth of melanoma cells.

CURCUMIN:  The yellow part of curry and mustard also stops melanoma in its tracks, at least in a petri dish.

CIMETADINE:  aka: tagamet, taken for heart burn, ulcers, etc, as it decreases stomach acid, helped get rid of melanoma in at least three horses.  There's a smattering of human "data" out there, too.

NSAID's:  Non steroidal anti-iflammatory drugs like Advil seem to decrease the risk of melanoma and squamous cell skin cancers.

SHIITAKES:  Good old Lentinula edodes mycelia!  If you're a mouse with melanoma and you have access to mushroom juice...you are in luck, my friend.

THE DATA:  Read at your own risk (the stuff on NAID's and Shiitakes I've posted before)!!

The protective effect of coffee consumption on cutaneous melanoma risk and the role of GSTM1 and GSTT1 polymorphisms.

Fortes C, Mastroeni S, Boffetta P, Antonelli G, Pilla MA, Bottà G, Anzidei P, Venanzetti F.

Source  Clinical Epidemiology Unit, Istituto Dermopatico dell'Immacolata, IDI-IRCSS, Via dei Monti di Creta, 104, 00167, Rome, Italy, c.fortes@idi.it.  2013 Jul 17. [Epub ahead of print]

Abstract

PURPOSES: The authors examined the association between coffee consumption and cutaneous melanoma and the implication of GSTM1 and GSTT1 polymorphisms.

METHODS: A hospital-based case-control study was conducted in the inpatient wards of IDI-San Carlo Rome, Italy, including 304 incident cases of cutaneous melanoma and 305 controls. Information on socio-demographic characteristics, medical history, smoking, sun exposure, pigmentary characteristics and diet was collected for all subjects. Within the study, individual patterns at two polymorphic genes (GSTM1 and GSTT1) belonging to glutathione S-transferases family were investigated in 188 cases of cutaneous melanoma and 152 controls. Logistic regression was the method used to estimate odds ratio and 95 % confidence intervals.

RESULTS: High frequency of coffee drinking (>once daily), compared with low-frequency consumption of coffee (≤7 times weekly) was associated with a protective effect for cutaneous melanoma (OR 0.46; 95 % CI 0.31-0.68) after adjusting for sex, age, education, hair colour, common nevi, skin phototype, and sunburn episodes in childhood. When stratified by GSTM1 and GSTT1 genotype, the protective effect of coffee was extremely high for subjects with both GSTM1 and GSTT1 null polymorphisms (OR 0.01; 95 % CI 0.0003-0.54).

CONCLUSIONS: Our results show a protective effect of coffee consumption for cutaneous melanoma, in particular for those with homozygous deletion for GSTM1 and GSTT1.

Doxycycline inhibits the adhesion and migration of melanoma cells by inhibiting the expression and phosphorylation of focal adhesion kinase (FAK). 

Sun T, Zhao N, Ni CS, Zhao XL, Zhang WZ, Su X, Zhang DF, Gu Q, Sun BC.  Source: Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China.Cancer Lett. 2009 Nov. Epub 209 May 30.

Abstract:  Doxycycline has been found to induce apoptosis and to inhibit the growth of a variety of tumor cells, in addition to its use as an antibiotic. However, the mechanism of its actions, especially at the molecular level, remains unknown and needs to be resolved. A crucial step possibly lies in the early period of doxycycline administration, which leads to a series of cascading effects depicting the consequential biological action of doxycycline on tumor cells. The present study focuses on the early-stage effects of doxycycline administration, specifically at the stages of treatment (before 16h). In this paper, we report that doxycycline inhibits the adhesion and migration of melanoma cells. Afterwards, the cells undergo apoptosis (aniokis). Remarkably, doxycycline also inhibits the expression and phosphorylation of focal adhesion kinase (FAK), a protein tyrosine kinase involved in the regulation of cell adhesion and migration. We further demonstrate that doxycycline down-regulates the activities of MMP-2 and MMP-9, and its effects are stronger than those of an Integrin beta1 antibody. Finally, we suggest that doxycycline might exert its anti-tumor effects by inhibiting FAK signaling pathway. These results provide an insight into the possible mechanisms that underlie the multiple drug actions of doxycycline. The potential use of doxycycline in anti-tumor treatment is promising and warrants further studies.

Activation of c-Jun N-terminal kinase is essential for mitochondrial membrane potential change and apoptosis induced by doxycycline in melanoma cells.

Shieh JM, Huang TF, Hung CF, Chou KH, Tsai YJ, Wu WB.  Source:  Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan.  Br J Pharmacol. 2010 Jul.

Abstract

BACKGROUND AND PURPOSE: Tetracyclines were recently found to induce tumour cell death, but the early processes involved in this cytotoxic effect remain unclear.

EXPERIMENTAL APPROACH: Viability of human and mouse melanoma cells was determined by MTT assay and flow cytometry. Kinase/protein/caspase activation was measured by Western blotting and mitochondrial membrane potential (DeltaPsi(m)) was analyzed by fluorescence microscopy and flow cytometry.

KEY RESULTS: Human and mouse melanoma cells were treated with doxycycline or minocycline but only doxycycline was cytotoxic. This cell death (apoptosis) in A2058 cells involved activation of caspase-3, -7 and -9 and contributed to inhibition, by doxycycline, of matrix metalloproteinase (MMP) activity and migration of these cells. Doxycycline induced intra-cellular reactive oxygen species (ROS) production, apoptosis signal-regulated kinase 1 (ASK1), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation at an early stage of treatment and induced mitochondrial cytochrome c release into cytosol and DeltaPsi(m) change during apoptosis. The JNK inhibitor/small interference RNA inhibited doxycycline-induced JNK activation, DeltaPsi(m) change and apoptosis, but did not affect ASK1 activation, suggesting a role of ASK1 for JNK activation in melanoma cell apoptosis. Two ROS scavengers reduced doxycycline-induced JNK and caspase activation, and apoptosis. Taken together, the results suggest the involvement of a ROS-ASK1-JNK pathway in doxycycline-induced melanoma cell apoptosis.

CONCLUSIONS AND IMPLICATIONS: We have shown a promising cytotoxic effect of doxycycline on melanoma cells, have identified ROS and ASK1 as the possible initiators and have demonstrated that JNK activation is necessary for doxycycline-induced melanoma cell apoptosis.

Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IκB kinase and nuclear factor κB activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway

Doris R. Siwak M.S., Shishir Shishodia Ph.D., Bharat B. Aggarwal Ph.D., Razelle Kurzrock M.D.^†,*  Article first published online: 11 JUL 2005

Abstract

BACKGROUND Nuclear factor-κB (NF-κB) plays a central role in cell survival and proliferation in human melanoma; therefore, the authors explored the possibility of exploiting NF-κB for melanoma treatment by using curcumin, an agent with known, potent, NF-κB-inhibitory activity and little toxicity in humans.

METHODS Three melanoma cell lines (C32, G-361, and WM 266-4), all of which had B-raf mutations, were treated with curcumin, and the authors assessed its effects on viability ((3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide assay) and apoptosis (flow-cytometric analysis of annexin V/propidium iodide-stained cells). Curcumin-treated cells also were examined for NF-κB binding activity (electrophoretic mobility shift assay) and for the activity of its upstream regulator, IκB kinase (IKK) (immune complex kinase assay). In addition, relevant signaling, as reflected by B-Raf kinase activity (kinase cascade assay), and steady-state levels of activated, downstream effectors, as reflected by mitogen-activated signal-regulated protein kinase (MEK), extracellular signal-regulated protein kinase (ERK), and Akt phosphorylation levels (immunoblots), were assessed.

RESULTS  Curcumin treatment decreased cell viability of all 3 cell lines in a dose-dependent manner (50% inhibitory concentration = 6.1–7.7 μM) and induced apoptosis.  However, curcumin did not inhibit the activities of B-Raf, MEK, or ERK, and Akt phosphorylation was enhanced. Furthermore, in the presence of curcumin, the Akt inhibitor 1L-6-hydroxymethyl-chiro-inositol 2-[(R)-2-O-methyl-3-O-octadecylcarbonate] no longer suppressed Akt phosphorylation.

CONCLUSIONS  Curcumin has potent antiproliferative and proapoptotic effects in melanoma cells. These effects were associated with the suppression of NF-κB and IKK activities but were independent of the B-Raf/MEK/ERK and Akt pathways. Cancer 2005.

Cimetidine for treatment of melanomas in three horses.

Goetz TE, Ogilvie GK, Keegan KG, Johnson PJ.  Source:  Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana 61801. J AM Vet Med Assoc. 1990

Abstract: Cimetidine, an H2 histamine antagonist, was used in the clinical management of progressive, multifocal melanomatosis in 3 adult gray horses. Prior to treatment, the tumors had increased rapidly in size and number in 2 horses (duration of 6 and 27 months, respectively) and slowly in the third horse (duration of 48 months). All 3 horses were treated with cimetidine (2.5 mg/kg of body weight, PO, q 8 h) for 2 months to 1 year. During treatment, the number and size of the melanomas decreased substantially (50 to 90%). The progression of the disease was halted in 2 horses and controlled in the third horse, which is still being treated with cimetidine (1.6 mg/kg, PO, q 24 h). The horses in which treatment was terminated have not been treated for 31 and 41 months, respectively, during which time the melanomas have not increased in number or size.

 

Nonsteroidal anti-inflammatory drugs and the risk of skin cancer:  A population-based case-control study. 

By:  Johannesdottir, Chang, Mehnert, et al.  In:  Cancer, 2012, May 29. [Epub]

Knowing that Nonsteroidal anti-inflammatory drugs (NSAIDS....like aspirin, ibuprofen, etc.) may prevent the development of cancer by inhibiting cyclooxygenase (COX) enzymes, these folks from Denmark looked at NSAID use and the risk of squamous cell carcinoma, basal cell carcinoma, and melanoma.  They looked at all cases of those diseases from 1991 through 2009 in northern Denmark. (Squamous = 1,974, basal = 13, 316, and melanoma = 3,242).  They matched 10 population controls (n=178,655) to each case by age, gender, and county of residence.  Use of NSAIDs was noted via a prescription data base.  FINDINGS:  After a great deal of incidence rate ratios and confidence interval statistical shenanigans....they determined that "NSAID ever use compared with nonuse was associated with a decreased risk of squamous cell and melanoma, especially for long-term use and high-intensity use.  NSAID use was not associated with a reduced risk of basal cell.  All estimates of reduced risk were driven primarily by the use of nonselective NSAIDs and older COX-2 inhibitors."

 

Oral ingestion of Lentinula edodes mycelia extract...in mice   

From:  Cancer Science, March, 2011
By:  Tanaka, Ishikawa, Matsui, et al., The Japanese Cancer Association.

Poor little mice "were inoculated subcutaneously in the footpad with B16 melanoma and fed L.E.M. extract [shiitake mushroom juice].  Ingestion of L.E.M. extract significantly inhibited tumor growth, and this in vivo anti-tumor effect was not observed in nude mice, suggesting a T cell-dependent mechanism. In addition, ingestion of [shiitake juice] led to significant restoration of H-2K(b)-restricted and melanoma-reactive T cells in the spleen and draining lymph nodes of melanoma bearing mice....furthermore, an in vitro assay revealed than an immunosuppressive activity of CD4(+) T cells from melanoma-bearing mice was canceled by ingestion of [shiitake juice].  Our results indicate that oral ingestion of L.E.M. extract restores immune responses of class 1-restricted and melanoma-reactive CD8(+) T cells in melanoma-bearing mice, presumably by a mitigation of regulatory T cells-mediated immunosuppression."