I was interested to see in the latest from the Mayo:
"Antidiabetic Effects of the Senolytic Agent Dasatinib" [1]
Many men with PCa are pre-diabetic at diagnosis, with some of the symptons of the metabolic syndrome [MetS]. Pre-diabetics do not necessarily progress to diabetes, but androgen deprivation increases the symptoms & severity of MetS. The result is an increase in the risk of cardiovascular events, if not actual diabetes. Senolytics aside, it would seem useful to have a drug that resists some of the morbidity of ADT.
Nalakrats mention Dasatinib a year ago [2]. (last para)
"Killing Dormant PCA Cells--->Senolytic Adaptations [Intro Part 1]"
"I will end this part with some recent news that a Senolytic combo of Dasatinib, and the supplement Quercetin, have been stopping certain undetectable cancer cells from dividing--not killing, which is what I prefer--but this is pretty heady stuff."
& 2 months ago, Purple-Bike had more to say about:
"Senolytic combo Dasatinib + Quercetin" [3[
Wikipedia [4]:
"Dasatinib has been shown to eliminate senescent cells in cultured adipocyte progenitor cells.[22] Dasatinib has been shown to induce apoptosis in senescent cells by inhibiting Src kinase, whereas quercetin inhibits the anti-apoptotic protein Bcl-xL.[22] Administration of dasatinib along with quercetin to mice improved cardiovascular function and eliminated senescent cells.[23] Aged mice given dasatinib with quercetin showed improved health and survival.[23]
"Giving dasatinib and quercetin to mice eliminated senescent cells and caused a long-term resolution of frailty.[24] A study of fourteen human patients suffering from idiopathic pulmonary fibrosis (a disease characterized by increased numbers of senescent cells) given dasatinib and quercetin showed improved physical function and evidence of reduced senescent cells."
There was a 2009 paper [5]:
"Phase II Study of Dasatinib in Patients with Metastatic Castration-Resistant Prostate Cancer"
I have pasted in the interesting Discussion section [5].
From 2013 [6]:
"Long-term use of dasatinib in patients with metastatic castration-resistant prostate cancer after receiving the combination of dasatinib and docetaxel"
"This brief report discusses in detail follow-up data on two patients who remain alive after >2.5 years on dasatinib single-agent therapy after discontinuing docetaxel treatment."
From 2019 [7]:
"Randomized Phase II Trial of Abiraterone Alone or With Dasatinib in Men With Metastatic Castration-resistant Prostate Cancer (mCRPC)"
"The Src family kinases have a proven role in tumorigenesis and in progression of various solid tumors, reviewed by Summy et al.19 Interactions of Src with AR and promotion of castration resistance, along with preclinical evidence of involvement by Src in the development of bone metastases, make it a target of great interest in mCRPC.5,9–11,20 Unfortunately, the addition of the Src inhibitor Das to AA in this study did not improve PFS, with the important caveat that an incomplete study cohort limited statistical power and the ability to draw conclusions. Nevertheless, these results are consistent with those of another study, a multi-arm protocol in which Das was added upon progression on AA and no benefit was identified.21 Furthermore, Das failed to prolong PFS when added to docetaxel in CRPC.22 Taken together, these data do not support the use of Das in an unselected population of patients with mCRPC."
"... the study did not clearly demonstrate that Src is a driver in CRPC, and a biomarker for Src-driven disease remains absent."
In 2013 [8], it was noted that:
"Increased serum insulin-like growth factor-1 levels are associated with prolonged response to dasatinib-based regimens in metastatic prostate cancer"
"In men with CRPC, an increase in IGF-1 levels after one cycle of treatment with dasatinib and docetaxel is associated with a higher response rate and longer duration of treatment."
From April [9]:
"Whole-Body [18F]-Fluoride PET SUV Imaging to Monitor Response to Dasatinib Therapy in Castration-Resistant Prostate Cancer Bone Metastases: Secondary Results from ACRIN 6687"
"The inability to observe a definitive relationship between changes in NaF PET uptake and PFS or OS may also be because the effect of dasatinib in mCRPC patients is marginal. Dasatinib has not been successful in demonstrating overall survival benefit in phase 3 trials of men with mCRPC [24]. Although the effects of dasatinib on bone have been clearly documented, it does not appear to offer significant anti-tumor efficacy [25,26]. The lack of association of changes in PET parameters to PFS or OS may be that the disease burden was so high in these mCRPC patients, that any response was buried in either PET measurement variability or dasatinib is an ineffective antineoplastic treatment against mCRPC."
***
I wonder if there might be a role for Dasatinib pre-CRPC?
Don't forget the quercetin!
-Patrick
[1] mayoclinicproceedings.org/a...
[2] healthunlocked.com/advanced...
[3] healthunlocked.com/advanced...
[4} en.wikipedia.org/wiki/Dasat...
[5] ncbi.nlm.nih.gov/pmc/articl...
Discussion.
Bone morbidity is a serious, debilitating complication for patients with CRPC. In this study, single-agent, twice daily dasatinib showed biological activity in chemotherapy-naive patients with CRPC as evidenced principally by bone biomarkers. Dasatinib produced reduction in BAP and uNTX in the majority of patients. Impressively, a significant proportion of men previously and concurrently receiving bisphosphonates had additional reduction in bone biomarkers in response to treatment with dasatinib. This is consistent with the proposed mechanism of action for dasatinib. Inhibition of SRC reduces osteoclast activity and results in inhibition of osteolysis. These data offer early hints that dasatinib may have bone effects in addition to that of bisphosphonates.
Beyond survival, there are other outcomes that are clinically important for patients with metastatic CRPC. Reduction of skeletal-related events and bone pain associated with bone metastases is an important goal, leading to significant improvement in quality of life. uNTX correlates with presence and extent of bone metastases (38), and an elevated uNTX level is an independent prognostic factor of reduced overall survival in patients with bone metastases from prostate cancer (9, 39–43). Normalization of uNTX is associated with a lower incidence of fractures, lower rate of bony disease progression, palliative response, and improved overall survival (36). In a subset analysis of CRPC patients, a 40% decrease in uNTX at 3 months resulted in ~17% reduction in the risk of death regardless of baseline uNTX levels (36). Although not validated as a surrogate marker for prostate cancer endpoints, changes in uNTX levels in response to therapy with dasatinib show signs of biological activity.
BAP also has important prognostic potential and offers information on osteoblastic activity separate from that provided by uNTX on osteoclastic activity. In an analysis of three large randomized trials of patients with bone metastases, high levels of BAP were associated with a significant increase in the risk of skeletal-related events compared with low BAP, and correlation was strongest for patients with prostate cancer (40). In a study of 31 patients with CPRC treated with docetaxel and atrasentan, an endothelin-A receptor antagonist, BAP, significantly declined with therapy and increased at the time of progression (44). Thus, in this study, dasatinib has shown effects on both osteoclastic and osteoblastic components of bone disease in prostate cancer, offering important hints of clinical relevance.
The bone effects and potential antitumor activity of dasatinib in prostate cancer are due, at least in part, to inhibition of SRC and other SFKs. Phase I studies have shown that exposures of dasatinib required to substantially inhibit SRC activity are achieved in patients with solid tumors (45). This study is the first clinical trial, to our knowledge, that shows inhibition of SRC to have biological activity through decrease in bone turnover biomarkers. Thus, dasatinib may have a future role for patients with prostate cancer as both an antitumor and a bone-targeted agent. We plan to further evaluate bone biomarkers and skeletal-related events as major endpoints in upcoming studies. Additionally, ongoing efforts are evaluating the efficacy of dasatinib in combination with docetaxel in CRPC. This is supported by preclinical models where dasatinib has synergistic effects with taxanes (19, 32). Early data from an ongoing phase I/II study are promising (46), and a large phase III, randomized, placebo-controlled trial of docetaxel with dasatinib is ongoing.
The original primary study endpoint, which was a composite response rate, was developed before PCWG2. However, in light of PCWG2 guidelines that phase II trials should expand the focus from measurement of response to determination of progression, we have also presented the lack of progression endpoint.
The original progression criteria also did not acknowledge new bone scan lesions in the absence of other clinical evidence of progression. Although there is much controversy and lack of standardization in reporting bone scan progression, PCWG2 recommends that it should be defined as two or more new lesions, confirmed by two or more new lesions on subsequent bone scans performed >6 weeks later. Because data on the number of new bone lesions were not collected and confirmatory bone scans were not always performed (as per the study protocol), we were unable to adopt this into our lack of progression analysis. As a result, the requirement for lack of progression in the current report is more stringent than PCWG2, as any new bone scan lesion was considered progression without additional confirmation.
In this study, single-agent dasatinib was reasonably well tolerated, with the majority of adverse events being mild or moderate and reversible with dose reduction or interruption. Although the development of pleural effusions was concerning in this patient population, subsequent reports of dasatinib used in combination with docetaxel in patients with metastatic CRPC reported only 7% of the entire population as developing pleural effusions (46). Although the biological mechanism is yet uncertain, the utilization of corticosteroids with docetaxel administration may have prevented the development of pleural effusion. Additionally, dasatinib was administered at a dose of 100 mg once daily rather than twice daily dosing. In hematologic malignancies, dasatinib 100 mg once daily provides responses similar to those in patients taking the approved 70 mg twice daily dose, with reduced incidence of side effects (34). It will be interesting to see if similar findings hold true in this population of prostate cancer patients, as subsequent patients (n = 47) in an ongoing study are being treated at a 100 mg daily dose.
In conclusion, the analysis of this study provides encouraging evidence of the activity and tolerability of dasatinib in chemotherapy-naive patients with metastatic CRPC. Our data with bone turnover biomarkers is the first to emphasize this unique mechanism of action from dasatinib-induced inhibition of SRC. It also introduces a novel therapy that may offer beneficial effects targeted to bone with the potential for dual antitumor activity. Dasatinib warrants further evaluation with both antitumor and skeletal morbidity endpoints, and efforts are ongoing.
[6] ncbi.nlm.nih.gov/pmc/articl...
[7] ncbi.nlm.nih.gov/pmc/articl...
From remission to recurrence
