Are drug delivery systems available in the market for folate receptor targeting? If folate targeting is successful, in what kind of tumors is it?
I would argue from my own review of this question, that the situation is considerably more promising - indeed I would say exciting - than suggested. Let me show why:
The folate receptor (FR) alpha is selectively overexpressed in several epithelial tumors, especially ovarian, endometrial, lung, renal, and breast carcinomas (and even in a few nonepithelial malignancies), and more particularly FR is overexpressed in >90% of ovarian cancers. Folate receptor−α (FR−α) is a membrane marker for ovarian cancer, and it is only recently, after over 20 years of laboratory research, that FR-targeted therapeutics are entering into the market, with I might add, considerable promise.
Right now, three human clinical trial FR-targeting agents are available, two entering Phase III trials after exhibiting clinical benefit in Phase I and Phase II trials, and of course in preclinical studies. The three are: (1) the monoclonal antibody farletuzumab (formerly MORAb-003); (2) the low molecular weight folic acid-vinca alkaloid conjugate, vintafolide (formerly EC145), and the folate receptor-targeting epothilone folate, BMS-753493, the first two - farletuzumab and vintafolide - being at Phase III.
As to farletuzumab, Phase I and II studies have demonstrated single agent and combination therapy efficacy with minimal toxicity. A phase II trial of farletuzumab plus carboplatin and a taxane was conducted in patients with platinum-sensitive epithelial ovarian cancer (EOC) in first relapse, showing an improved response rate and time to progression (TTP) compared with historical controls, while preliminary safety data from a phase I trial reported that the combination of farletuzumab, carboplatin and a new-generation anthracycline, namely pegylated liposomal doxorubicin (PLD; Doxil/Caelyx) demonstrated an acceptable safety profile in patients with platinum- sensitive EOC after first or second relapse. The Phase III development plan in ovarian cancer patients includes combination chemotherapy studies in both platinum-sensitive and platinum-resistant (planned) recurrent disease. And besides its efficacy in epithelial ovarian cancer (EOC), farletuzumab is also being explored in lung cancer: an ongoing phase II trial is evaluating farletuzumab in patients with FOLR1 expressing metastatic adenocarcinoma of lung.
Thee second folate receptor-targeting agent, vintafolide (EC145) is a conjugate of folic acid and the vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), related to vinblastine, has been found safe and with evidence of efficacy in several malignancies, especially advanced epithelial ovarian cancer (EOL) and non–small-cell lung cancer (NSCLC). It is often deployed with FR-targeted EC20 imaging, a technetium-labeled folate that assesses the presence of folate receptors (FR) in vivo, where EC20 imaging identifies those patients with advanced ovarian cancer, or with chemotherapy refractory lung adenocarcinoma, most likely to benefit from therapy with FR-targeted vintafolide, as demonstrated by Martin Edelman and colleagues at the University of Maryland Greenebaum Cancer Center, at ASCO 2010 (also reported recently in JCO 2012).
Preliminary data from a phase II clinical trial, called the PRECEDENT Trial, in patients with advanced ovarian cancer demonstrated that third- or fourth-line vintafolide therapy provided better disease control than second- or third-line liposomal doxorubicin (PLD), and that the coadministration of vintafolide and liposomal doxorubicin (PLD) produced a statistically significant increase in progression-free survival (PFS) over standard therapy in patients with platinum-resistant ovarian cancer, indeed there was a greater than 2-fold increase in median PFS with the addition of vintafolide (24 weeks vs 11.7 weeks HR 0.50, p=0.014) in platinum-resistant ovarian cancer, a ground-breaking finding in this highly challenging malignancy. And just strating accrual, the Phase III randomized international PROCEED Trial is exploring the efficacy of the combination vintafolide + PLD in platinum-resistant ovarian cancer patients expressing FR. There is also a multicenter trial of vintafolide in advanced, folate-receptor positive adenocarcinoma of the lung.
The third FR-targeting agent - that is, with human clinical, not just preclinical, data - is the epothilone folate BMS-753493, but findings to date are minimal: BMS-753493 was evaluated in two parallel first-in-human phase I/II studies in subjects with advanced solid cancers, but demonstrated at best moderate activity with manageable toxicity, however with no objective responses.
At this time, therefore, in my accelerated review of FR-targeting interventions, I find vintafolide (EC145) especially, and farletuzumab (MORAb-003), the most promising, and at this stage it is not clear if the third agent, BMS-753493, will move forward in the pipeline. And although there are several other FR-targeting agents in development, they as yet lack human clinical evidence of efficacy and safety.
It is long-overdue that this promising cancer target, folate receptor (FR), is finally after a couple of decades of dormancy in laboratories, showing its exceptional promise through two robust FR-targeting agents (vintafolide and farletuzumab), and I predict that in the not too distant future, clinical benefit may be seen in several other malignancies.
Yes, of course, folate-based targeting is highly attractive and interested in recent years for drug targeting. The main focus in this field is on solid tumors, particularly those loacated in deep and not easily accessible parts of the body. However, there should be a definite steategy and nanostructure in such a study. Both polymeric and lipid-based nanoparticles as well as dendrimers have been attempted in recent years.
thank u Prof Mehrdad.....is there any dosage form available in the international market which is targeted for folate receptors?
To the best of my knowledge, there is no marketed pharmaceutical based on folate targeting. However, there may be something in pipelines. I have to check.
Goo luck. Good luck.
I would argue from my own review of this question, that the situation is considerably more promising - indeed I would say exciting - than suggested. Let me show why:
The folate receptor (FR) alpha is selectively overexpressed in several epithelial tumors, especially ovarian, endometrial, lung, renal, and breast carcinomas (and even in a few nonepithelial malignancies), and more particularly FR is overexpressed in >90% of ovarian cancers. Folate receptor−α (FR−α) is a membrane marker for ovarian cancer, and it is only recently, after over 20 years of laboratory research, that FR-targeted therapeutics are entering into the market, with I might add, considerable promise.
Right now, three human clinical trial FR-targeting agents are available, two entering Phase III trials after exhibiting clinical benefit in Phase I and Phase II trials, and of course in preclinical studies. The three are: (1) the monoclonal antibody farletuzumab (formerly MORAb-003); (2) the low molecular weight folic acid-vinca alkaloid conjugate, vintafolide (formerly EC145), and the folate receptor-targeting epothilone folate, BMS-753493, the first two - farletuzumab and vintafolide - being at Phase III.
As to farletuzumab, Phase I and II studies have demonstrated single agent and combination therapy efficacy with minimal toxicity. A phase II trial of farletuzumab plus carboplatin and a taxane was conducted in patients with platinum-sensitive epithelial ovarian cancer (EOC) in first relapse, showing an improved response rate and time to progression (TTP) compared with historical controls, while preliminary safety data from a phase I trial reported that the combination of farletuzumab, carboplatin and a new-generation anthracycline, namely pegylated liposomal doxorubicin (PLD; Doxil/Caelyx) demonstrated an acceptable safety profile in patients with platinum- sensitive EOC after first or second relapse. The Phase III development plan in ovarian cancer patients includes combination chemotherapy studies in both platinum-sensitive and platinum-resistant (planned) recurrent disease. And besides its efficacy in epithelial ovarian cancer (EOC), farletuzumab is also being explored in lung cancer: an ongoing phase II trial is evaluating farletuzumab in patients with FOLR1 expressing metastatic adenocarcinoma of lung.
Thee second folate receptor-targeting agent, vintafolide (EC145) is a conjugate of folic acid and the vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), related to vinblastine, has been found safe and with evidence of efficacy in several malignancies, especially advanced epithelial ovarian cancer (EOL) and non–small-cell lung cancer (NSCLC). It is often deployed with FR-targeted EC20 imaging, a technetium-labeled folate that assesses the presence of folate receptors (FR) in vivo, where EC20 imaging identifies those patients with advanced ovarian cancer, or with chemotherapy refractory lung adenocarcinoma, most likely to benefit from therapy with FR-targeted vintafolide, as demonstrated by Martin Edelman and colleagues at the University of Maryland Greenebaum Cancer Center, at ASCO 2010 (also reported recently in JCO 2012).
Preliminary data from a phase II clinical trial, called the PRECEDENT Trial, in patients with advanced ovarian cancer demonstrated that third- or fourth-line vintafolide therapy provided better disease control than second- or third-line liposomal doxorubicin (PLD), and that the coadministration of vintafolide and liposomal doxorubicin (PLD) produced a statistically significant increase in progression-free survival (PFS) over standard therapy in patients with platinum-resistant ovarian cancer, indeed there was a greater than 2-fold increase in median PFS with the addition of vintafolide (24 weeks vs 11.7 weeks HR 0.50, p=0.014) in platinum-resistant ovarian cancer, a ground-breaking finding in this highly challenging malignancy. And just strating accrual, the Phase III randomized international PROCEED Trial is exploring the efficacy of the combination vintafolide + PLD in platinum-resistant ovarian cancer patients expressing FR. There is also a multicenter trial of vintafolide in advanced, folate-receptor positive adenocarcinoma of the lung.
The third FR-targeting agent - that is, with human clinical, not just preclinical, data - is the epothilone folate BMS-753493, but findings to date are minimal: BMS-753493 was evaluated in two parallel first-in-human phase I/II studies in subjects with advanced solid cancers, but demonstrated at best moderate activity with manageable toxicity, however with no objective responses.
At this time, therefore, in my accelerated review of FR-targeting interventions, I find vintafolide (EC145) especially, and farletuzumab (MORAb-003), the most promising, and at this stage it is not clear if the third agent, BMS-753493, will move forward in the pipeline. And although there are several other FR-targeting agents in development, they as yet lack human clinical evidence of efficacy and safety.
It is long-overdue that this promising cancer target, folate receptor (FR), is finally after a couple of decades of dormancy in laboratories, showing its exceptional promise through two robust FR-targeting agents (vintafolide and farletuzumab), and I predict that in the not too distant future, clinical benefit may be seen in several other malignancies.
Thanks Constantine Kaniklidis for enlightening about the folate targeted molecules faltzumab and vintafolide. Its really a perfect update for us. i will go through on Martin paper in JCO ...thanks a lot for info.
Venkatachalam: Glad it will be of help.
In that connection, I thought you may also appreciate this concise collection of of the most seminal and landmark references for the benefits of FR-targeting in the human clinical setting, and they in turn refer to still earlier preclinical studies should you need them (I have also included the hyperlinks to the online sources for your convenience). They constitute collectively the best literature to start with in any research endeavor into this question.
Good luck!
References: Human Clinical Data on FR-Targeting:
Nunez MI, Behrens C, Woods DM, et al. High expression of folate receptor alpha in lung cancer correlates with adenocarcinoma histology and EGFR [corrected] mutation. J Thorac Oncol 2012; 7(5):833-40.
http://journals.lww.com/jto/Abstract/2012/05000/High_Expression_of_Folate_Receptor_Alpha_in_Lung.10.aspx
Spannuth WA, Sood AK, Coleman RL. Farletuzumab in epithelial ovarian carcinoma. Expert Opin Biol Ther 2010; 10(3):431-7.
http://informahealthcare.com/doi/abs/10.1517/14712591003592069
Jelovac D, Armstrong DK. Role of farletuzumab in epithelial ovarian carcinoma. Curr Pharm Des 2012; 18(25):3812-5.
http://www.ingentaconnect.com/content/ben/cpd/2012/00000018/00000025/art00023
Konner JA, Bell-McGuinn KM, Sabbatini P, et al. Farletuzumab, a humanized monoclonal antibody against folate receptor alpha, in epithelial ovarian cancer: a phase I study. Clin Cancer Res 2010 Nov 1; 16(21):5288-95.
http://clincancerres.aacrjournals.org/content/16/21/5288.full
Lorusso PM, Edelman MJ, Bever SL, et al. Phase I study of folate conjugate EC145 (Vintafolide) in patients with refractory solid tumors. J Clin Oncol 2012 Nov 10; 30(32):4011-6.
http://jco.ascopubs.org/content/30/32/4011
Li J, Sausville EA, Klein PJ, et al.
Clinical pharmacokinetics and exposure-toxicity relationship of a folate-Vinca alkaloid conjugate EC145 in cancer patients. J Clin Pharmacol. 2009 Dec;49(12):1467-76. doi: 10.1177/0091270009339740. Epub 2009 Oct 16.
http://jcp.sagepub.com/content/49/12/1467.full
Symanowski JT, Maurer AH, Naumann RW, et al. Use of 99mTc-EC20 (a folate-targeted imaging agent) to predict response to therapy with EC145 (folate-targeted therapy) in advanced ovarian cancer. J Clin Oncol (Meeting Abstracts) May 2010 vol. 28 no. 15_suppl 5034.
http://meeting.ascopubs.org/cgi/content/abstract/28/15_suppl/5034
Edelman MJ, Harb WA, Pal SE, et al. Multicenter trial of EC145 in advanced, folate-receptor positive adenocarcinoma of the lung. J Thorac Oncol 2012; 7(10):1618-21.
http://journals.lww.com/jto/Abstract/2012/10000/Multicenter_Trial_of_EC145_in_Advanced,.20.aspx
Naumann RW, Coleman RL, Burger RA et al. PRECEDENT: a randomized Phase II trial comparing EC145 and pegylated liposomal doxorubicin (PLD) in combination, versus PLD alone, in subjects with platinum-resistant ovarian cancer. J. Clin. Oncol.29(Suppl.), Abstract 5045 (2011).
http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=51046
De Jonge MJ, Sleijfer S, Martin LP, et al. Phase I pharmacokinetic and safety analysis of epothilone folate (BMS-753493): First-in-human clinical experience of a folate receptor-targeted chemotherapeutic agent administered on days 1, 4, 8, and 11 of a 21-day cycle.
J Clin Oncol (Meeting Abstracts) May 2010 vol. 28 no. 15_suppl 2607.
http://meeting.ascopubs.org/cgi/content/abstract/28/15_suppl/2607.
Thanks for the collective literature on folate targeting. it will be definitely helpful in my studies.
Very good and constructive discussion, also for myself. I am sure this discussion will be very useful for Venkatachalam and the most eminent benefit of the communities like Researchgate is this fruitful communications in the way to improve the global research trends. However, I do not mentioned in my previous answer that the situation is not promising. Of course it is promising. I said no product is already in market. Good luck
Mehrdad:
My apologies if I misstated it: I do understand that you were only claiming the lack of approved on-the-marker FR-targeting agents, and didn't mean to imply otherwise. Thanks for the clarification.
Constantine
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