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Argos starts Phase II clinical trial with Dendritic Cell Immunotherapy AGS-003 in Non Small Cell Lung Cancer in conjunction with standard platinum therapy
Reporter: Stephen J. Williams, Ph.D.
Argos Announces Start of Phase II AGS-003 Trial in NSCLC
News | March 28, 2016 | Lung Cancer Targets
By Bryant Furlow
The Cancer Research Network of Nebraska has initiated a phase II clinical trial of the autologous dendritic cell immunotherapy AGS-003 with standard platinum-doublet chemotherapy, for non-small cell lung cancer (NSCLC), Argos Therapeutics, Inc. has announced.
AGS-003 is produced using RNA from a patient’s tumor sample, and dendritic cells. It is designed to provoke memory T-cell immune responses specifically targeting an individual patient’s tumor neoantigens, which arise from tumor-specific gene mutations.
“The standard of treatment of NSCLC has been chemotherapy after surgery, but now we can offer this exciting new option of individualized immunotherapy,” said co-principal investigator Stephen Lemon, MD, Oncology Associates in Omaha.
The nonrandomized, open-label, phase II safety study will enroll 20 patients newly diagnosed with stage III NSCLC, administering AGS-003 either concurrently or sequentially with standard carboplatin and paclitaxel chemotherapy regimens, with or without radiotherapy. The primary study endpoint is the effect of AGS-003 on the toxicity associated with standard chemotherapy. Secondary endpoints include memory T-cell activation among patients who complete induction therapy and are administered five or more doses of AGS-003.
AGS-003 is also under study in the phase III ADAPT clinical trial for patients with metastatic renal cell carcinoma (mRCC). Argos is an immuno-oncology firm developing and commercializing “truly individualized” anticancer immunotherapies.
New Generation of Platinated Compounds to Circumvent Resistance
Curator/Writer: Stephen J. Williams, Ph.D.
Resistance to chemotherapeutic drugs continues to be a major hurdle in the treatment of neoplastic disorders, irregardless if the drug is a member of the cytotoxic “older” drugs or the cytostatic “newer” personalized therapies like the tyrosine kinase inhibitors. For the platinatum compounds such as cisplatin and carboplatin, which are mainstays in therapeutic regimens for ovarian and certain head and neck cancers, development of resistance is often regarded as the final blow, as new options for these diseases have been limited.
Although there are many mechanisms by which resistance to platinated compounds may develop the purpose of this posting is not to do an in-depth review of this area except to refer the reader to the book Ovarian Cancer and just to summarize the well accepted mechanisms of cisplatin resistance including:
Decreased cellular cisplatin influx
Increased cellular cisplatin efflux
Increased cellular glutathione and subsequent conjugation, inactivation
Increased glutathione-S-transferase activity (GST) and subsequent inactivation, conjugation
Increased γ-GGT
Increased metallothionenes with subsequent conjugation, inactivation
Increased DNA repair: increased excision repair
DNA damage tolerance: loss of mismatch repair (MMR)
altered cell signaling activities and cell cycle protein expression
Williams, S.J., and Hamilton, T.C. Chemotherapeutic resistance in ovarian cancer. In: S.C. Rubin, and G.P. Sutton (eds.), Ovarian Cancer, pp.34-44. Lippincott, Wilkins, and Williams, New York, 2000.
Also for a great review on clinical platinum resistance by Drs. Maritn, Hamilton and Schilder please see the following Clinical Cancer Research link here.
This curation represents the scientific rationale for the development of a new class of platinated compounds which are meant to circumvent mechanisms of resistance, in this case the loss of mismatch repair (MMR) and increased tolerance to DNA damage.
An early step in the production of cytotoxicity by the important anticancer drug cisplatin and its analog carboplatin is the formation of intra- and inter-strand adducts with tumor cell DNA 1-3. This damage triggers a cascade of events, best characterized by activation of damage-sensing kinases (reviewed in 4), p53 stabilization, and induction of p53-related genes involved in apoptosis and cell cycle arrest, such as bax and the cyclin-dependent kinase inhibitor p21waf1/cip1/sdi1 (p21), respectively 5,6. DNA damage significantly induces p21 in various p53 wild-type tumor cell lines, including ovarian carcinoma cells, and this induction is responsible for the cell cycle arrest at G1/S and G2/M borders, allowing time for repair 7,8. DNA lesions have the ability of to result in an opening of chromatin structure, allowing for transcription factors to enter 56-58. Therefore the anti-tumoral ability of cisplatin and other DNA damaging agents is correlated to their ability to bind to DNA and elicit responses, such as DNA breaks or DNA damage responses which ultimately lead to cell cycle arrest and apoptosis. Therefore either repair of such lesions, the lack of recognition of such lesions, or the cellular tolerance of such lesions can lead to resistance of these agents.
Mechanisms of Cisplatin Sensitivity and Resistance. Red arrows show how a DNA lesion results in chemo-sensitivity while the beige arrow show common mechanisms of resistance including increased repair of the lesion, effects on expression patterns, and increased inactivation of the DNA damaging agent by conjugation reactions
Increased DNA Repair Mechanisms of Platinated Lesion Lead to ChemoResistance
Description of Different Types of Cellular DNA Repair Pathways. Nucleotide Excision Repair is commonly up-regulated in highly cisplatin resistant cells
Loss of Mismatch Repair Can Lead to DNA Damage Tolerance
In the following Cancer Research paper Dr. Vaisman in the lab of Dr. Steve Chaney at North Carolina (and in collaboration with Dr. Tom Hamilton) describe how cisplatin resistance may arise from loss of mismatch repair and how oxaliplatin lesions are not recognized by the mismatch repair system.
Defects in mismatch repair are associated with cisplatin resistance, and several mechanisms have been proposed to explain this correlation. It is hypothesized that futile cycles of translesion synthesis past cisplatin-DNA adducts followed by removal of the newly synthesized DNA by an active mismatch repair system may lead to cell death. Thus, resistance to platinum-DNA adducts could arise through loss of the mismatch repair pathway. However, no direct link between mismatch repair status and replicative bypass ability has been reported. In this study, cytotoxicity and steady-state chain elongation assays indicate that hMLH1 or hMSH6 defects result in 1.5-4.8-fold increased cisplatin resistance and 2.5-6-fold increased replicative bypass of cisplatin adducts. Oxaliplatin adducts are not recognized by the mismatch repair complex, and no significant differences in bypass of oxaliplatin adducts in mismatch repair-proficient and -defective cells were found. Defects in hMSH3 did not alter sensitivity to, or replicative bypass of, either cisplatin or oxaliplatin adducts. These observations support the hypothesis that mismatch repair defects in hMutL alpha and hMutS alpha, but not in hMutS beta, contribute to increased net replicative bypass of cisplatin adducts and therefore to drug resistance by preventing futile cycles of translesion synthesis and mismatch correction.
The following are slides I had co-prepared with my mentor Dr. Thomas C. Hamilton, Ph.D. of Fox Chase Cancer Center on DNA Mismatch Repair, Oxaliplatin and Ovarina Cancer.
Multiple Platinum Analogs of Cisplatin (like Oxaliplatin )Had Been Designed to be Sensitive in MMR Deficient Tumors
Please see below video on 2015 Nobel Laureates and their work to elucidate the celluar DNA repair mechanisms.
Clinical genetics expert Kenneth Offit gives an overview of Lynch syndrome, a genetic disorder that can cause colon (HNPCC) and other cancers by defects in the MSH2 DNA mismatch repair gene. (View Video)
References
Johnson, S. W. et al. Relationship between platinum-DNA adduct formation, removal, and cytotoxicity in cisplatin sensitive and resistant human ovarian cancer cells. Cancer Res54, 5911-5916 (1994).
Eastman, A. The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes. Pharmacology and Therapeutics34, 155-166 (1987).
Zhen, W. et al. Increased gene-specific repair of cisplatin interstrand cross-links in cisplatin-resistant human ovarian cancer cell lines. Molecular and Cellular Biology12, 3689-3698 (1992).
Durocher, D. & Jackson, S. P. DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr Opin Cell Biol13, 225-231 (2001).
el-Deiry, W. S. p21/p53, cellular growth control and genomic integrity. Curr Top Microbiol Immunol227, 121-37 (1998).
Ewen, M. E. & Miller, S. J. p53 and translational control. Biochim Biophys Acta1242, 181-4 (1996).
Gartel, A. L., Serfas, M. S. & Tyner, A. L. p21–negative regulator of the cell cycle. Proc Soc Exp Biol Med213, 138-49 (1996).
Chang, B. D. et al. p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene19, 2165-70 (2000).
Davies, N. P., Hardman, L. C. & Murray, V. The effect of chromatin structure on cisplatin damage in intact human cells. Nucleic Acids Res28, 2954-2958 (2000).
Vichi, P. et al. Cisplatin- and UV-damaged DNA lure the basal transcription factor TFIID/TBP. Embo J16, 7444-7456 (1997).
Xiao, G. et al. A DNA damage signal is required for p53 to activate gadd45. Cancer Res60, 1711-9 (2000).
Other articles in this Open Access Journal on ChemoResistance Include:
Nitric oxide (NO), a gas with many biological functions in healthy cells, has also been implicated in the development of pathologies such as cancer. Nitric oxide may also play a role in chemotherapeutic reisitance. For example it had been known (in the 1996 Melanoma study by Joshi et al. curated below) that nitric oxide synthase activity (the enzyme system which produces NO) was significantly elevated in cultured melanoma cell lines versus normal melanocytes. Although it is known that many protein and enzymes systems could be directly covalently-modified by nitric oxide, either by S-nitrosylation or NO-NAD+ modifications (one of my earlier postings described one such protein modified by nitric oxide, GAPDH, and the effect these NO-modifications of GAPDH has on the etiology of various pathologies.), the molecular mechanisms by which these modifications affect cellular processes, lead to disease etiology, the proteins which are affected, and mechanisms related to chemotherapeutic sensitivity need to be further characterized. A new study from MIT reveals how NO-induced modifications may reduce cisplatin sensitivity in melanoma cells. This study focuses on how decreasing nitric oxide levels in melanoma cells increases their cisplatin sensitivity. The study also describes a possible mechanism for this effect: NO-induced modifications of the proapoptotic enzyme caspace-3 and prolyl-hdroxylase-2 (responsible for targeting prosurvival HIF-1α for proteosomal degradation). Also, for a description of other cancer-related targets of nitric oxide please see the posting by Dr. Saxena at Crucial role of Nitric Oxide in Cancer on this site.
It is important, however, to note that most of these relationships between NO-induced protein modification and its relationship to disease mechanisms are causal, meaning that, in general, one notices a nitric-induced modification of a protein/enzyme with concomitant alteration of protein/enzyme function occurring in a disease/phenotype. However, unlike reversible modifications, which have a cadre of pharmacologic inhibitors, nitric oxide induced modifications are covalent and nonenzymatic, therefore hindering easy cause/effect relationships.
The findings from Dr. Luiz Godoy’s PNAS paper ENDOGENOUSLY PRODUCED NITRIC OXIDE MITIGATES SENSITIVITY OF MELANOMA CELLS TO CISPLATIN, were presented at the 2013 annual meeting of the American Association for Cancer Research. The prognosis is generally worse for patients whose tumors have high levels of NO, said Luiz Godoy, an MIT research associate and lead author of the study.
Godoy and his colleagues have unraveled the mechanism behind melanoma’s resistance to cisplatin, a commonly used chemotherapy drug, and, in ongoing studies, have found that cisplatin treatment also increases NO levels in breast and colon cancers.
“This could be a mechanism that is widely shared in different cancers, and if you use the drugs that are already used to treat cancer, along with other drugs that could scavenge or decrease the production of NO, you may have a synergistic effect,” said Godoy, who works in the lab of Gerald Wogan, an MIT professor emeritus of biological engineering and senior author of the study.
NO has many roles within living cells. At low concentrations, it helps regulate processes such as cell death and muscle contraction. NO, which is a free radical, is also important for immune-system function. Immune cells, such as macrophages, produce large amounts of NO during infection, helping to kill invading microbes by damaging their DNA or other cell components.
“It’s really a molecule that has a dual effect,” Godoy said. “At low concentrations it can act as a signaling molecule, while high concentrations will be toxic.”
Knocking out NO
In the new study, the researchers treated melanoma cells grown in the lab with drugs that capture NO before it can act. They then treated the cells with cisplatin and tracked cell-death rates. The NO-depleted cells became much more sensitive to the drug, confirming earlier findings.
The MIT team then went a step further, investigating how NO confers its survival benefits. It was already known that NO can alter protein function through a process known as S-nitrosation, which involves attaching NO to the target protein. S-nitrosation can affect many proteins, but in this study the researchers focused on two that are strongly linked with cell death and survival, known as caspase-3 and PHD2.
The role of caspase-3 is to stimulate cell suicide, under the appropriate conditions, but adding NO to the protein deactivates it. This prevents the cell from dying even when treated with cisplatin, a drug that produces massive DNA damage.
PHD2 is also involved in cell death; its role is to help break down another protein called HIF-1 alpha, which is a pro-survival protein. When NO inactivates PHD2, HIF-1 alpha stays intact and keeps the cell alive.
“Now we have a mechanistic link between nitric oxide and the increased aggressiveness of melanoma,” said Douglas Thomas, an assistant professor of medicinal chemistry and pharmacognosy at the University of Illinois at Chicago, who was not part of the research team. “It certainly would be worth exploring whether this mechanism is also present in different tumor types as well.”
The MIT researchers also found in some cancer cells, NO levels were five times higher than normal following cisplatin treatment. Godoy is now investigating how cisplatin stimulates that NO boost, and is also looking for other proteins that NO may be targeting.
Department of Dermatology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA.
Abstract
Nitric oxide (NO) may be an important mediator of tumour angiogenesis and metastasis formation. Tumour cell derived NO may be important in the regulation of angiogenesis and vasodilatation of the blood vessels surrounding a tumour. The aims of the present study were, firstly, to determine whether malignant melanoma cells and normal melanocytes had nitric oxide synthase (NOS) activity (measured by the conversion of L-arginine to L-citrulline) and, secondly, to determine whether there was a difference in NOS activity between malignant and normal cell types. This paper assays NOS activity directly in lysates from normal human melanocyte and malignant melanoma cell lines. The enzyme activity was not inducible with bacterial lipopolysaccharide and could be heat denatured. The activity of NOS was demonstrated to be both NADPH- and calcium-dependent and it was inhibitable in a dose-dependent manner by the NOS inhibitor Nw-nitro-L-arginine methyl ester. We conclude that melanoma and melanocyte cells express a constitutive form of NOS. Finally, nitric oxide synthase activity in melanoma cell lines was found to be significantly greater than in normal melanocytes. These findings suggest that NO synthesis is elevated in malignant melanoma. An elevated NO concentration in melanoma is expected to promote metastases by maintaining a vasodilator tone in the blood vessels in and around the melanoma.
Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20373-8. doi: 10.1073/pnas.1218938109. Epub 2012 Nov 26.
Endogenously produced nitric oxide mitigates sensitivity of melanoma cells to cisplatin.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract
Melanoma patients experience inferior survival after biochemotherapy when their tumors contain numerous cells expressing the inducible isoform of NO synthase (iNOS) and elevated levels of nitrotyrosine, a product derived from NO. Although several lines of evidence suggest that NO promotes tumor growth and increases resistance to chemotherapy, it is unclear how it shapes these outcomes. Here we demonstrate that modulation of NO-mediated S-nitrosation of cellular proteins is strongly associated with the pattern of response to the anticancer agent cisplatin in human melanoma cells in vitro. Cells were shown to express iNOS constitutively, and to generate sustained nanomolar levels of NO intracellularly. Inhibition of NO synthesis or scavenging of NO enhanced cisplatin-induced apoptotic cell death. Additionally, pharmacologic agents disrupting S-nitrosation markedly increased cisplatin toxicity, whereas treatments favoring stabilization of S-nitrosothiols (SNOs) decreased its cytotoxic potency. Activity of the proapoptotic enzyme caspase-3 was higher in cells treated with a combination of cisplatin and chemicals that decreased NO/SNOs, whereas lower activity resulted from cisplatin combined with stabilization of SNOs. Constitutive protein S-nitrosation in cells was detected by analysis with biotin switch and reduction/chemiluminescence techniques. Moreover, intracellular NO concentration increased significantly in cells that survived cisplatin treatment, resulting in augmented S-nitrosation of caspase-3 and prolyl-hydroxylase-2, the enzyme responsible for targeting the prosurvival transcription factor hypoxia-inducible factor-1α for proteasomal degradation. Because activities of these enzymes are inhibited by S-nitrosation, our data thus indicate that modulation of intrinsic intracellular NO levels substantially affects cisplatin toxicity in melanoma cells. The underlying mechanisms may thus represent potential targets for adjuvant strategies to improve the efficacy of chemotherapy.
Other posts on this site regarding Nitric Oxide and Cancer include:
Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin (Translating Basic Research to the Clinic)
Author/Writer: Stephen J. Williams, Ph.D.
This will be a regular posting which I hope people will find interesting. I wish to highlight the basic research which led to seminal breakthroughs in the medical field, brought on by the result of basic inquiry, thorough and detailed investigation, meticulously following the scientific method, and eventually leading to development of important medical therapies.
This month I would like to highlight the research of Dr. Barnett Rosenberg and his discovery of one of the most used and effective chemotherapeutics, cisplatin.
The compound cis-PtCl2(NH3)2 (seen in the Figure ) was first described by M. Peyrone in 1845, and known for a long time as Peyrone’s salt.[3] In 1965, Barnett Rosenberg, van Camp et al. of Michigan State University had asked a simple question and noticed that electrical fields can inhibit the division and induce filamentous growth of Escherichia coli (E. coli) bacteria. . Although bacterial cell growth continued, cell division was arrested, the bacteria growing as filaments up to 300 times their normal length.[5]However, Dr. Roenberg did not stop at this finding and meticulously accounting for each variable which might explain this finding, including altering the metal composistion of the electrodes. Dr. Rosenberg thought of the possibility it was not the electric field perse, which caused the growth inhibition, but a chemical produced in the media by electrolysis. Eventually he discovered that electrolysis of platinum electrodes generated a soluble platinum complex which inhibited binary fission in Escherichia coli (E. coli) bacteria. In addition he isolated this platinum complex and discovered that ammonium ions were required as well, owing to the full chemical structure of cisplatin as seen above (the nitrogens moieties are bioactivated to cations). This finding led to the observation that cis PtCl2(NH3)2 was indeed highly effective at regressing the mass of sarcomas in rats.[8] Confirmation of this discovery, and extension of testing to other tumour cell lines launched the medicinal applications of cisplatin. Cisplatin was approved for use in testicular and ovarian cancers by the U.S. Food and Drug Administration on December 19, 1978.[9]
^ Peyrone M. (1844). “Ueber die Einwirkung des Ammoniaks auf Platinchlorür”. Ann Chemie Pharm51 (1): 1–29. doi:10.1002/jlac.18440510102.
^ Rosenberg, B.; Van Camp, L.; Krigas, T. (1965). “Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode”. Nature205 (4972): 698–699. doi:10.1038/205698a0. PMID14287410.
In 1965, Rosenberg and his colleagues proved that certain platinum-containing compounds inhibited cell division and then in 1969 showed that they cured solid tumors. The chemotherapy drug that eventually resulted from this work, cisplatin, obtained US Food and Drug Administration (FDA) approval in 1978 and went on to become a widely used anticancer drug. The initial discovery was quite serendipitous. Rosenberg was looking into the effects of an electric field on the growth of bacteria. He noticed that bacteria ceased to divide when placed in an electric field and eventually pinned down the cause of this phenomenon to the platinum electrode he was using.[2]
^ Rosenberg, B.; Van Camp, L.; Krigas, T. (1965). “Inhibition of Cell Division in Escherichia coli by Electrolysis Products from a Platinum Electrode”. Nature205 (4972): 698–9. doi:10.1038/205698a0. PMID14287410. edit
Non-small Cell Lung Cancer drugs – where does the Future lie?
In focus: Tarceva, Avastin and Dacomitinib
UPDATED on July 5, 2013
(from reports published in New England Journal of Medicine on drug, crizotinib)
Curator: Ritu Saxena, Ph.D.
Introduction
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and usually grows and spreads more slowly than small cell lung cancer.
There are three common forms of NSCLC:
Adenocarcinomas are often found in an outer area of the lung.
Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus).
Large cell carcinomas can occur in any part of the lung. They tend to grow and spread faster than the other two types.
Lung cancer is by far the leading cause of cancer death among both men and women. Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined. The American Cancer Society’s most recent estimates for lung cancer in the United States for 2012 reveal that about 226,160 new cases of lung cancer will be diagnosed (116,470 in men and 109,690 in women), and there will be an estimated 160,340 deaths from lung cancer (87,750 in men and 72,590 among women), accounting for about 28% of all cancer deaths.
Treatment
Different types of treatments are available for non-small cell lung cancer. Treatment depends on the stage of the cancer. For patients in whom the cancer has not spread to nearby lymph nodes are recommended surgery. Surgeon may remove- one of the lobes (lobectomy), only a small portion of the lung (wedge removal), or the entire lung (pneumonectomy). Some patients require chemotherapy that uses drugs to kill cancer cells and stop new cells from growing.
On the basis of target, the drugs have been classified as follows:
NSCLC Drug Market Analysis
NSCLC drug market expected to grow from $4.2 billion in 2010 to $5.4 billion in 2020
Although, a whole list of agents is available for the treatment of NSCLC, the market for NSCLC drugs is expected to expand from $4.2 billion in 2010 to $5.4 billion in 2020 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan.
However, drug sales for metastatic/advanced squamous cell non-small-cell lung cancer, which comprises only a small fraction of the market, will decrease from nearly 17 percent in 2010 to approximately 13 percent in 2020. According to surveyed U.S. oncologists and MCO pharmacy directors, increasing overall survival is one of the greatest unmet needs in first-line advanced squamous non-small-cell lung cancer.
In 2009, antimetabolites dominated the NSCLC market, with Eli Lilly’s Alimta (Pemetrexed) accounting for nearly three-quarters of sales within this drug class. Since then, Alimta has faced tough competition from a number of similar drugs and from emerging therapies. It was speculated that the antimetabolites market share would reduce significantly making it the second-largest drug class in NSCLC, while the epidermal growth factor receptor (EGFR) inhibitor class will garner the top market share by 2019.
Genentech/OSI Pharmaceuticals/Roche/Chugai Pharmaceutical’s Tarceva belongs to the EGFR inhibitor class, and has been prescribed principally along with Eli Lilly’s Alimta, to NSCLC patients.Both these drugs have dominated the NSCLC market till 2010, however, their market hold is expected to weaken from 2015-2020, as claimed by Decision Resources Analyst Karen Pomeranz, Ph.D. Decision Resources is a research and advisory firms for pharmaceutical and healthcare issues.
Tarceva (Erlotinib)
Generic Name: Erlotinib, Brand Name: Tarceva
Other Designation: CP 358774, OSI-774, R1415, RG1415, NSC 718781
Mechanism of Action: Tarceva, a small molecule quinazoline, directly and reversibly inhibits the epidermal growth factor receptor (EGFr) tyrosine kinase. Detailed information on how it works could be found at the Macmillian Cancer support website.
Tarceva has been approved for different cancers and several indications have been filed-
non-small cell lung cancer (nsclc), locally advanced or metastatic, second line, after failure of at least one prior chemotherapy regimen (2004)
pancreatic cancer, locally advanced or metastatic, in combination with gemcitabine, first line (2005)
non-small cell lung cancer (nsclc), advanced, maintenance therapy in responders following first line treatment with platinum-based chemotherapy (2010)
non-small cell lung cancer (nsclc) harboring epidermal growth factor (EGFr)-activating mutations, first line treatment in advanced disease
Sales of Tarceva
May, 2012 sales of Tarceva in the US have been reported to be around $564.2 million.
In a recent article published by Vergnenègre et al in the Clinicoeconomic Outcomes Research journal (2012), cross-market cost-effectiveness of Erlotinib was analyzed. The study aimed at estimating the incremental cost-effectiveness of Erlotinib (150 mg/day) versus best supportive care when used as first-line maintenance therapy for patients with locally advanced or metastatic NSCLC and stable disease.
It was determined that treatment with erlotinib in first-line maintenance resulted in a mean life expectancy of 1.39 years in all countries, compared with a mean 1.11 years with best supportive care, which represents 0.28 life-years (3.4 life-months) gained with erlotinib versus best supportive care.
According to the authors analysis, there was a gain in the costs per-life year as $50,882, $60,025, and $35,669 in France, Germany, and Italy, respectively. Hence, on the basis of the study it was concluded that Erlotinib is a cost-effective treatment option when used as first-line maintenance therapy for locally advanced or metastatic NSCLC.
Avastin (Bevacizumab)
Generic Name: Avastin, Brand Name: Bevacizumab
Other Designation: rhuMAb-VEGF, NSC-704865, R435, RG435
Mechanism of Action
Bevacizumab is a recombinant humanized Mab antagonist of vascular endothelial growth factor A (VEGFA) acting as an angiogenesis inhibitor.
Avastin is the only currently approved VEGF inhibitor that selectively targets VEGF-A.
Three other approved oral drugs, pazopanib (Votrient; GlaxoSmithKline), sunitinib (Sutent; Pfizer) and sorafenib (Nexavar; Onyx Pharmaceuticals) are orally available multi-targeted receptor tyrosine kinase inhibitors that include VEGF receptors among their targets.
Avastin has been approved for different cancers and several indications have been filed:
colorectal cancer, advanced, metastatic, first line, in combination with a 5-FU based chemotherapy regimen
colorectal cancer, relapsed, metastatic, second line, in combintion with 5-FU-based chemotherapy (2004)
non-small cell lung cancer (nsclc), non-squamous, inoperable, locally advanced, recurrent or metastatic, in combination with carboplatin and paclitaxel chemotherapy, first line (2006)
breast cancer, chemotherapy naive, first line, locally recurrent or metastatic, in combination with taxane chemotherapy (2008, revoked in 2011)
non-small cell lung cancer (nsclc), non-squamous, inoperable, locally advanced, recurrent or metastatic, in combination with platinum-based chemotherapy, first line
renal cell carcinoma (RCC), metastatic, in combination with interferon (IFN) alpha, first line (2009)
glioblastoma multiforme (GBM), relapsed after first line chemoradiotherapy
breast cancer, chemotherapy naive, first line, locally recurrent or metastatic, HEr2 negative, in combination with capecitabine (2009)
ovarian cancer, in combination with standard chemotherapy (carboplatin and paclitaxel) as a first line treatment following surgery for women with advanced (Stage IIIb/c or Stage IV) epithelial ovarian, primary peritoneal or fallopian tube cancer
ovarian cancer, in combination with carboplatin and gemcitabine as a treatment for women with recurrent, platinum-sensitive ovarian cancer
As of May, 2012, sales of Avastin in the US have been reported to be around $2.66 billion.
It attracted a lot of attention over the past few years after its use as a breast cancer treatment. Avastin was approved by the FDA under its fast-track program. However, the data released by the FDA from follow-up studies led to questioning the use of Avastin as a breast cancer drug. Infact, Genentech pulled the indication from Avastin’s label. Henceforth, the FDA did cancel that approval in late 2011. Doctors, however, can still prescribe it off-label. Potential adverse effects of Avastin that came under scrutiny along with unfavorable cost benefit analyses might pose challenges to its growth potential and continued widespread use. However, the sales of Avastin have continued to increase and it has been reported by Fierce Pharma as one of the 15 best-selling cancer drugs list. (Fierce Pharma)
Dacomitinib: New promising drug for NSCLC
Generic Name: Dacomitinib
Other Designation: PF-299804, PF-00299804, PF-299,804, PF00299804
PF-299804 is an orally available irreversible pan-HEr tyrosine kinase inhibitor.
Dacomitinib is a promising new drug on the market. Phase III trials are ongoing for advanced and refractory NSCLC, locally advanced or metastatic NSCLC and the EGFr mutation containing locally advanced or metastatic NSCLC in several countries including those in Europe, Asia, and America.
Dacomitinib bests Erlotinib in advanced NSCLC: Comparison of its Progression-Free Survival (PFS) with the NSCLC marketed drug, Erlotinib.
In September of 2012, a study was published by Ramalingam et al in the Journal of Clinical Oncology, which was a randomized open-label trial comparing dacomitinib with erlotinib in patients with advanced NSCLC. On the basis of the study it was concluded that dacomitinib demonstrated significantly improved progression-free survival (PFS*) as compared to erlotinib, with a certain degree of toxicity.
Median PFS was significantly greater with Dacomitinib than Erlotinib, at 2.86 versus 1.91.
Mean duration of response was 16.56 months for dacomitinib and 9.23 months for erlotinib.
Patients were divided into groups by tumor type and following results were obtained:
Median PFS was 3.71 months with dacomitinib and 1.91 with erlotinib in patients with KRAS wild-type tumors
Median PFS was 2.21 months and 1.68 months, in patients with KRAS wild-type/EGFR wild-type tumors.
PFS was significantly better in the molecular subgroups harboring a mutant EGFR genotype.
The study also highlighted the side effects which might be more of concern and probably limiting for Dacomitinib.
Although adverse side effects were uncommon in both the groups, certain side effects such as:
mouth sores,
nailbed infections, and
diarrhea
were more common and tended to be more severe with Dacomitinib as compared to Tarceva.
Therefore, for patients for whom side effects of Tarceva seem challenging might face more difficulty with Dacomitinib treatment. Nonetheless, the results of PFS were promising enough and provide a greater efficacy in several clinical and molecular subgroups targeting a larger population than Tarceva. Authors, thus, suggested a larger, randomized phase III trial with the same design.
Current status of Dacomitinib
Based on positive performance of Dacomitinib published in research studies, Pfizer has entered into a collaborative development agreement with the SFJ Pharmaceuticals Group to conduct a phase III clinical trial across multiple sites in Asia and Europe, to evaluate dacomitinib (PF-00299804) as a first line treatment in patients with locally advanced or metastatic non-small cell lung cancer (nsclc) with activating mutations in the epidermal growth factor receptor (EGFr). Under the terms of the agreement, SFJ will provide the funding and clinical development supervision to generate the clinical data necessary to support a registration dossier on Dacomitinib for marketing authorization by regulatory authorities for this indication. If approved for this indication, SFJ will be eligible to receive milestone and earn-out payments.
*PFS or Progression-free survival is defined as the length of time during and after the treatment of as disease, such as cancer, that a patient lives with the disease but it does not get worse. In a clinical trial, measuring the progression-free survival is one way to see how well a new treatment works.
Recently, another drug PF-02341066 (crizotinib), was tested on patients with non-small cell lung cancer and the results were published in New England Journal of Medicine (2013). Crizotinibis an orally available aminopyridine-based inhibitor of the) and the c-Met/hepatocyte growth factor receptor (HGFR). Crizotinib, in an ATP-competitive manner, binds to and inhibits ALK kinase and ALK fusion proteins. In addition, crizotinib inhibits c-Met kinase, and disrupts the c-Met signaling pathway. Altogether, this agent inhibits tumor cell growth.
Shaw and colleagues (2013) investigated whether crizotinib is superior to standard chemotherapy with respect to efficacy. To answer the question, Pfizer launched a phase III clinical trial (NCT00932893; http://clinicaltrials.gov/show/NCT00932893) comparing the safety and anti-tumor activity of PF-02341066 (crizotinib) versus pemetrexed or docetaxel in patients with advanced non-small cell lung cancer harboring a translocation or inversion event involving the ALK gene. Shaw and colleagues (2013) published the results of the clinical trial in a recent issue of New England Journal of Medicine. A total of 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen were recruited for the trial and patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. According to the results, the median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group. Hazard ratio (HR) for progression or death with crizotinib was 0.49 (95% CI, P<0.001). The response rates were 65% with crizotinib, as compared with 20% with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy.In conclusion, the results from the trial indicate that crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non–small-cell lung cancer with ALK rearrangement. (Shaw AT, et al, Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med 2013; 20 June, 368:2385-2394; http://www.ncbi.nlm.nih.gov/pubmed/23724913).
However, in the same issue of New England Journal of Medicine, Awad and colleagues (2013) reported from a phase I clinical trial (NCT00585195; http://clinicaltrials.gov/show/NCT00585195), that a patient with metastatic lung adenocarcioma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment, showed resistance to crizotinib. Biopsy of the resistant tumor identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the metastatic sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. The study was funded by Pfizer (Awad MM, et al, Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med. 2013 Jun 20;368(25):2395-401; http://www.ncbi.nlm.nih.gov/pubmed/23724914)
Nitric oxide (NO) is a lipophilic, highly diffusible and short-lived molecule that acts as a physiological messenger and has been known to regulate a variety of important physiological responses including vasodilation, respiration, cell migration, immune response and apoptosis. Jordi Muntané et al
NO is synthesized by the Nitric Oxide synthase (NOS) enzyme and the enzyme is encoded in three different forms in mammals: neuronal NOS (nNOS or NOS-1), inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3). The three isoforms, although similar in structure and catalytic function, differ in the way their activity and synthesis in controlled inside a cell. NOS-2, for example is induced in response to inflammatory stimuli, while NOS-1 and NOS-3 are constitutively expressed.
Regulation by Nitric oxide
NO is a versatile signaling molecule and the net effect of NO on gene regulation is variable and ranges from activation to inhibition of transcription.
The intracellular localization is relevant for the activity of NOS. Infact, NOSs are subject to specific targeting to subcellular compartments (plasma membrane, Golgi, cytosol, nucleus and mitochondria) and that this trafficking is crucial for NO production and specific post-translational modifications of target proteins.
Role of Nitric oxide in Cancer
One in four cases of cancer worldwide are a result of chronic inflammation. An inflammatory response causes high levels of activated macrophages. Macrophage activation, in turn, leads to the induction of iNOS gene that results in the generation of large amount of NO. The expression of iNOS induced by inflammatory stimuli coupled with the constitutive expression of nNOS and eNOS may contribute to increased cancer risk. NO can have varied roles in the tumor environment influencing DNA repair, cell cycle, and apoptosis. It can result in antagonistic actions including DNA damage and protection from cytotoxicity, inhibiting and stimulation cell proliferation, and being both anti-apoptotic and pro-apoptotic. Genotoxicity due to high levels of NO could be through direct modification of DNA (nitrosative deamination of nucleic acid bases, transition and/or transversion of nucleic acids, alkylation and DNA strand breakage) and inhibition of DNA repair enzymes (such as alkyltransferase and DNA ligase) through direct or indirect mechanisms. The Multiple actions of NO are probably the result of its chemical (post-translational modifications) and biological heterogeneity (cellular production, consumption and responses). Post-translational modifications of proteins by nitration, nitrosation, phosphorylation, acetylation or polyADP-ribosylation could lead to an increase in the cancer risk. This process can drive carcinogenesis by altering targets and pathways that are crucial for cancer progression much faster than would otherwise occur in healthy tissue.
NO can have several effects even within the tumor microenvironment where it could originate from several cell types including cancer cells, host cells, tumor endothelial cells. Tumor-derived NO could have several functional roles. It can affect cancer progression by augmenting cancer cell proliferation and invasiveness. Infact, it has been proposed that NO promotes tumor growth by regulating blood flow and maintaining the vasodilated tumor microenvironment.NO can stimulate angiogenesis and can also promote metastasis by increasing vascular permeability and upregulating matrix metalloproteinases (MMPs). MMPs have been associated with several functions including cell proliferation, migration, adhesion, differentiation, angiogenesis and so on. Recently, it was reported that metastatic tumor-released NO might impair the immune system, which enables them to escape the immunosurveillance mechanism of cells. Molecular regulation of tumour angiogenesis by nitric oxide.
S-nitrosylation and Cancer
The most prominent and recognized NO reaction with thiols groups of cysteineresidues is called S-nitrosylation or S-nitrosation, which leads to the formation of more stable nitrosothiols. High concentrations of intracellular NO can result in high concentrations of S-nitrosylated proteins and dysregulated S-nitrosylation has been implicated in cancer. Oxidative and nitrosative stress is sensed and closely associated with transcriptional regulation of multiple target genes.
Following are a few proteins that are modified via NO and modification of these proteins, in turn, has been known to play direct or indirect roles in cancer.
NO mediated aberrant proteins in Cancer
Bcl2
Bcl-2 is an important anti-apoptotic protein. It works by inhibiting mitochondrial Cytochrome C that is released in response to apoptotic stimuli. In a variety of tumors, Bcl-2 has been shown to be upregulated, and it has additionally been implicated with cancer chemo-resistance through dysregulation of apoptosis. NO exposure causes S-nitrosylation at the two cysteine residues – Cys158 and Cys229 that prevents ubiquitin-proteasomal pathway mediated degradation of the protein. Once prevented from degradation, the protein attenuates its anti-apoptotic effects in cancer progression. The S-nitrosylation based modification of Bcl-2 has been observed to be relevant in drug treatment studies (for eg. Cisplatin). Thus, the impairment of S-nitrosylated Bcl-2 proteins might serve as an effective therapeutic target to decrease cancer-drug resistance.
p53
p53 has been well documented as a tumor suppressor protein and acts as a major player in response to DNA damage and other genomic alterations within the cell. The activation of p53 can lead to cell cycle arrest and DNA repair, however, in case of irrepairable DNA damage, p53 can lead to apoptosis. Nuclear p53 accumulation has been related to NO-mediated anti-tumoral properties. High concentration of NO has been found to cause conformational changes in p53 resulting in biological dysfunction.. In RAW264.7, a murine macrophage cell line, NO donors induce p53 accumulation and apoptosis through JNK-1/2.
HIF-1a
Hypoxia-inducible factor 1 (HIF1) is a heterodimeric transcription factor that is predominantly active under hypoxic conditions because the HIF-1a subunit is rapidly degraded in normoxic conditions by proteasomal degradation. It regulates the transciption of several genes including those involved in angiogenesis, cell cycle, cell metabolism, and apoptosis. Hypoxic conditions within the tumor can lead to overexpression of HIF-1a. Similar to hypoxia-mediated stress, nitrosative stress can stabilize HIF-1a. NO derivatives have also been shown to participate in hypoxia signaling. Resistance to radiotherapy has been traced back to NO-mediated HIF-1a in solid tumors in some cases.
PTEN
Phosphatase and tensin homolog deleted on chromosome ten (PTEN), is again a tumor suppressor protein. It is a phosphatase and has been implicated in many human cancers. PTEN is a crucial negative regulator of PI3K/Akt signaling pathway. Over-activation of PI3K/Akt mediated signaling pathway is known to play a major role in tumorigenesis and angiogenesis. S-nitrosylation of PTEN, that could be a result of NO stress, inhibits PTEN. Inhibition of PTEN phosphatase activity, in turn, leads to promotion of angiogenesis.
C-Src
C-src belongs to the Src family of protein tyrosine kinases and has been implicated in the promotion of cancer cell invasion and metastasis. It was demonstrated that S-nitrosylation of c-Src at cysteine 498 enhanced its kinase activity, thus, resulting in the enhancement of cancer cell invasion and metastasis.
Jaiswal M, et al. Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis. Am J Physiol Gastrointest Liver Physiol. 2001 Sep;281(3):G626-34. http://www.ncbi.nlm.nih.gov/pubmed/11518674
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