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Some proposed changes to Tipifarnib

[edit]

Tipifarnib is an experimental drug in development for the treatment of certain kinds of cancer. It is a small-molecule inhibitor of the enzyme, farnesyltransferase, and a member of a class of drug candidates called farnesyltransferase inhibitors. Tipifarnib was originally developed by Janssen Pharmaceutica NV, an affiliate of Johnson & Johnson, and was licensed in 2014 to Kura Oncology for further development in oncology.[1] Kura Oncology’s license was expanded to all therapeutic areas other than virology in 2016.

Molecular Mechanism of Action

Many proteins involved in cellular signaling must be associated with other proteins at the inner cellular membrane of the tumor cell to function properly. The enzyme farnesyltransferase catalyzes the attachment of a 15-carbon isoprenoid unit to the carboxyl terminus of a protein, facilitating association with the cell membrane.[2]This text is insufficiently paraphrased from the source material.

Tipifarnib blocks activity of the farnesyltransferase enzyme. Treatment of tumors with tipifarnib results in the reversal of several hallmarks of cancer, including mitotic arrest, induction of apoptosis, growth inhibition, invasion, angiogenesis and tumor growth, as well as induction of tumor regression in animal models.[3][4]The text in at least one of the indicated sources does not support this statement.

Activity in HRAS Mutant Solid Tumors

One gene implicated in the development and progression of certain tumors is HRAS (Harvey rat sarcoma viral oncogene homolog).[5][6]The page number given for one of these sources does not correspond to page numbers from the actual source. HRAS is a proto-oncogene, which is a normal gene that can become an oncogene due to mutations or increased expression. HRAS is mutated and/or over-expressed in certain tumors.

The HRAS protein is localized in the plasma membrane and is an early player in many signal transduction pathways. In certain tumors, mutations in HRAS or its upstream regulators result in persistent activation of downstream growth and proliferation signals that drive tumor cell growth.[7]The text located here cites Wikipedia as its source.

The HRAS protein requires farnesylation for its association with the cellular membrane and proper function. Tipifarnib prevents the farnesylation of the HRAS protein and, thus, it has the potential for therapeutic benefit by blocking the activity of tumors that are driven by mutant HRAS.

Clinical Development

Tipifarnib was initially developed by Janssen and has been studied in more than 5,000 patients. It was observed to be generally well tolerated with a manageable side effect profile as a single agent.[8]

In clinical studies in the late 1990s and early 2000s, tipifarnib demonstrated a well-established safety profile and durable anti-cancer activity in certain patients. Johnson and Johnson submitted an application to FDA for approval of tipifarnib in elderly patients with newly diagnosed poor-risk acute myeloid leukemia, but it received a non-approvable letter in 2005.[9][10]

Although tipifarnib demonstrated evidence of clinical benefit, it was never studied in a genetically-enriched patient population. Clinical and preclinical data suggest that, in certain selected patient populations, tipifarnib has the potential to provide significant benefit to cancer patients with limited treatment options.[11]

Since in-licensing tipifarnib from Janssen in 2014, Kura Oncology has undertaken an effort to identify biomarkers associated with the activity of tipifarnib that could help to identify those patients most likely to benefit from treatment.[12] The company is currently studying the drug candidate in multiple Phase 2 clinical trials.

In July 2017, Kura Oncology announced that the United States Patent and Trademark Office had issued U.S. Patent No. 9,707,221, entitled “Methods of Treating Cancer Patients with Farnesyltransferase Inhibitors.” The patent includes multiple claims directed to the use of tipifarnib in patients with HRAS mutant squamous cell carcinoma of the head and neck (SCCHN) and has an expiration date of August 2036, excluding any possible patent term extension.

In September 2017, Kura Oncology announced positive topline results from a Phase 2 trial for tipifarnib in patients with HRAS mutant relapsed or refractory squamous cell carcinomas of the head and neck (HNSCC).[13] Laurenruthfish (talk) 18:57, 19 October 2017 (UTC)[reply]

References

  1. ^ "Home - Kura Oncology". Kura Oncology.
  2. ^ Reid, TS; Terry, KL; Casey, PJ; Beese, LS (October 2004). "Crystallographic analysis of CaaX prenyltransferases complexed with substrates defines rules of protein substrate selectivity". J. Mol. Biol. 343 (2): 417. {{cite journal}}: More than one of |pages= and |page= specified (help)
  3. ^ Cox; et al. (April 2015). "Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?". Clin. Cancer Res. 21 (8): 1819. {{cite journal}}: Explicit use of et al. in: |first1= (help); More than one of |pages= and |page= specified (help)
  4. ^ Berndt; et al. (November 2011). "Targeting protein prenylation for cancer therapy". Nature Reviews Cancer. 11: 775. {{cite journal}}: Explicit use of et al. in: |first1= (help); More than one of |pages= and |page= specified (help)
  5. ^ Wong-Staal, F; Dalla-Favera, R; Franchini, G; Gelmann, EP; Gallo, RC (July 1981). "Three distinct genes in human DNA related to the transforming genes of mammalian sarcoma retroviruses". Science. 213 (4504).
  6. ^ Russell, MW; Munroe, DJ; Bric, E; Housman, DE; Dietz-Band, J; Riethman, HC; Collins, FS; Brody, LC (July 1996). "A 500-kb physical map and contig from the Harvey ras-1 gene to the 11p telomere". Genomics. 35 (2): 353. {{cite journal}}: More than one of |pages= and |page= specified (help)
  7. ^ "HRAS". Wikipedia. 31 August 2017.
  8. ^ http://www.kuraoncology.com/wp-content/uploads/2017/08/Alan-Ho-MD-TAT2017.pdf. {{cite web}}: Missing or empty |title= (help)
  9. ^ https://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4138B1_01_J&J-Briefing-Document.pdf. {{cite web}}: Missing or empty |title= (help)
  10. ^ http://www.firstwordpharma.com/node/192918#axzz4vFU5xrdV. {{cite web}}: Missing or empty |title= (help)
  11. ^ http://www.kuraoncology.com/wp-content/uploads/2017/08/Alan-Ho-MD-TAT2017.pdf. {{cite web}}: Missing or empty |title= (help)
  12. ^ "Press Releases - Investor Relations - Kura Oncology". ir.kuraoncology.com.
  13. ^ "BRIEF-Kura Oncology announces positive phase 2 study for Tipifarnib in HRAS mutant head and neck cancer". Reuters. 2017.
I've posted feedback into the article above. Please feel free to review it at your earliest convenience. When you are ready, kindly reactivate your request by changing the edit request template parameter marked "ans" from "ans=yes" to "ans=no" Regards,  Spintendo  ᔦᔭ  22:07, 16 December 2017 (UTC)[reply]
I will add to this, that generally we avoid self-generated sources like press releases and the company website. There are decent trade rag sources like Fierce Biotech, Bioworld, and Xconcomy that report on the biotech industry, and business-oriented local papers like the San Diego UT (for Kura) may have stuff. For the science, we use secondary sources like reviews, not primary sources (e.g. research papers). So much depends on the sources you start with. Jytdog (talk) 00:03, 17 December 2017 (UTC)[reply]
Thanks for this helpful feedback and for reviewing the content I'd proposed. I've had some time to review the Wikipedia editing guidelines, and I have a couple of changes to the Tipifarnib page that I'd like to suggest on this Talk page that comply with the guidelines (unlike what I'd proposed before), and help to maintain the accuracy of the page. Before I go ahead and make those suggestions, I'd like to make sure that I can dismiss the content I'd suggested before, and propose my new comments below this thread? Thanks! Laurenruthfish (talk) 23:20, 13 July 2018 (UTC)[reply]

Some Proposed Changes to Tipifarnib, Part II

[edit]

Tipifarnib (INN,[1]:213 proposed trade name Zarnestra) is a farnesyltransferase inhibitor that is being investigated in patients with HRAS mutant head and neck cancer, peripheral T-cell lymphoma (PTCL), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).[1][2][3][4][5]

Protein farnesylation (a type of prenylation) is a post-translational modification required for the activity of many oncogenic proteins, including Ras kinase.[6] Tipifarnib blocks the activity of the farnesyltransferase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive.[7]

HISTORY

The compound was first discovered by Janssen (formerly known as Johnson & Johnson Pharmaceutical Research & Development, L.L.C), with registration number R115777. Janssen tested tipifarnib in a variety of solid tumors and myeloid malignancies, including breast, colorectal, lung, brain, pancreatic and urothelial cancers.[8]

For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I sponsored by the National Cancer Institute, tipifarnib successfully passed phase I clinical trials but was suspended (NCT00029354) after phase II.[9][10]

Janssen investigated tipifarnib in patients 65 years of age and older with newly diagnosed acute myeloid leukemia (AML) and submitted a new drug application (NDA) to the FDA on January 24, 2005. In June 2005, the FDA issued a “not approvable” letter for tipifarnib.[11]

Kura Oncology in-licensed tipifarnib from Janssen in 2014, and the former is currently investigating its therapeutic potential in select, genetically-defined patient populations.[12][13]Laurenruthfish (talk) 22:22, 29 August 2018 (UTC)[reply]

References

  1. ^ Witzig, Thomas E.; Tang, Hui; Micallef, Ivana N. M.; Ansell, Stephen M.; Link, Brian K.; Inwards, David J.; Porrata, Luis F.; Johnston, Patrick B.; Colgan, Joseph P.; Markovic, Svetomir N.; Nowakowski, Grzegorz S.; Thompson, Carrie A.; Allmer, Cristine; Maurer, Matthew J.; Gupta, Mamta; Weiner, George; Hohl, Ray; Kurtin, Paul J.; Ding, Husheng; Loegering, David; Schneider, Paula; Peterson, Kevin; Habermann, Thomas M.; Kaufmann, Scott H. (3 November 2011). "Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas". Blood. 118 (18): 4882. doi:10.1182/blood-2011-02-334904. ISSN 0006-4971.
  2. ^ "Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations | ClinicalTrials.gov". www.clinicaltrials.gov. 10 March 2015.
  3. ^ "Study of Tipifarnib in Subjects With Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL) | ClinicalTrials.gov". www.clinicaltrials.gov. 12 October 2017.
  4. ^ "Tipifarnib in Subjects With Myelodysplastic Syndromes | ClinicalTrials.gov". www.clinicaltrials.gov. 20 May 2016.
  5. ^ "Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia (CMML) | ClinicalTrials.gov". www.clinicaltrials.gov. 12 October 2017.
  6. ^ Berndt, Norbert; Hamilton, Andrew D.; Sebti, Saïd M. (November 2011). "Targeting protein prenylation for cancer therapy". Nature Reviews Cancer. 11 (11): 775–791. doi:10.1038/nrc3151. ISSN 1474-175X.
  7. ^ Cox, Adrienne D.; Der, Channing J.; Philips, Mark R. (15 April 2015). "Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?". Clinical Cancer Research. 21 (8): 1821. doi:10.1158/1078-0432.CCR-14-3214. ISSN 1078-0432.
  8. ^ Mesa, Ruben A (10 January 2014). "Tipifarnib: farnesyl transferase inhibition at a crossroads". Expert Review of Anticancer Therapy. 6 (3): 313. doi:10.1586/14737140.6.3.313.
  9. ^ Lara, Primo N.; Law, Lisa Y.; Wright, John J.; Frankel, Paul; Twardowski, Przemyslaw; Lenz, Heinz Josef; Lau, Derick H. M.; Kawaguchi, Tomoya; Gumerlock, Paul H.; Doroshow, James H.; Gandara, David R. (March 2005). "Intermittent dosing of the farnesyl transferase inhibitor tipifarnib (R115777) in advanced malignant solid tumors: a phase I California Cancer Consortium Trial". Anti-Cancer Drugs. 16 (3): 317}. doi:10.1097/00001813-200503000-00011. ISSN 0959-4973.
  10. ^ Widemann, B. C.; Dombi, E.; Gillespie, A.; Wolters, P. L.; Belasco, J.; Goldman, S.; Korf, B. R.; Solomon, J.; Martin, S.; Salzer, W.; Fox, E.; Patronas, N.; Kieran, M. W.; Perentesis, J. P.; Reddy, A.; Wright, J. J.; Kim, A.; Steinberg, S. M.; Balis, F. M. (4 February 2014). "Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas". Neuro-Oncology. 16 (5): 716. doi:10.1093/neuonc/nou004. ISSN 1522-8517.
  11. ^ Thomas, Xavier (December 2007). "Tipifarnib in the treatment of acute myeloid leukemia". Biologics: Targets & Therapy. 1 (4): 421.
  12. ^ Carroll, John (12 March 2015). "Kura sheds stealth mode with $60M for PhII cancer drug licensed from J&J | FierceBiotech". www.fiercebiotech.com.
  13. ^ Chen, X; Makarewicz, J M; Knauf, J A; Johnson, L K; Fagin, J A (18 November 2013). "Transformation by HrasG12V is consistently associated with mutant allele copy gains and is reversed by farnesyl transferase inhibition". Oncogene. 33 (47): 5442. doi:10.1038/onc.2013.489. ISSN 0950-9232.


Reply 16-AUG-2018

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   Clarification needed   Please clarify the following, in order to better process your request:

  1. The reference article's DOI numbers. I have entered the DOI's for the links you've provided.
  2. In order to verify the claims made here, please provide the reference article's exact page numbers where the information resides (shown above in the reference section in red font)
  3. Please provide a verbatim description of any text to be deleted.
  4. The First Word Pharma source could not be confirmed. Please provide an alternate reference.

When ready to proceed, please change the request template's answer parameter to read from ans=yes to ans=no. Thank you!  spintendo  22:32, 16 August 2018 (UTC)[reply]

Reply 29-AUG 2018

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I have included page numbers for each article where the information could be found. I included ClinicalTrials.gov links to verify that the clinical trials are taking place--is this sufficient information (given that it is a government-run website), or will I need to find different sources? I also included a new source to prove Janssen's FDA rejection of tipifarnib (the "Biologics" journal), however, I was unable to locate the doi number online.

The text to be deleted:

-"patients 65 years of age and older with newly diagnosed acute myeloid leukemia (AML)." This is incorrect because it is outdated information.

-"It inhibits the Ras kinase in a post-translational modification step before the kinase pathway becomes hyperactive. It inhibits prenylation of the CaaX tail motif, which allows Ras to bind to the membrane where it is active. Without this step the protein cannot function." I rephrased this in order to be more in line with the sources used.

-"It is also being tested in clinical trials in patients in certain stages of breast cancer.[2] It is also investigated as a treatment for multiple myeloma." Outdated information

-"The compound was discovered by and is under investigation by Johnson & Johnson Pharmaceutical Research & Development, L.L.C, with registration number R115777." Rephrased to make sure this is more current.

Please let me know if this information is sufficient, or if any additional changes need to be made. Thank you!

Laurenruthfish(talk) 22:22, 29 August 2018 (UTC)[reply]

Reply to edit request "Part II" 09-SEP-2018

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Below you will see where proposals from your request have been quoted with reviewer decisions and feedback inserted underneath, either accepting, declining or otherwise commenting upon your proposal(s). Please read the enclosed notes for information on each request.  spintendo  06:29, 9 September 2018 (UTC)[reply]

Edit Request Review section 09-SEP-2018

Tipifarnib (INN,[1]:213 proposed trade name Zarnestra) is a farnesyltransferase inhibitor that is being investigated in patients with HRAS mutant head and neck cancer, peripheral T-cell lymphoma (PTCL), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).
 Approved.Cite error: There are <ref> tags on this page without content in them (see the help page).

___________
Protein farnesylation (a type of prenylation) is a post-translational modification required for the activity of many oncogenic proteins, including Ras kinase.
no Declined.[note 1]

___________
Tipifarnib blocks the activity of the farnesyltransferase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive.
 Partly approved.[note 2]

___________
The compound was first discovered by Janssen (formerly known as Johnson & Johnson Pharmaceutical Research & Development, L.L.C), with registration number R115777.
 Already done.[note 3]

___________
Janssen tested tipifarnib in a variety of solid tumors and myeloid malignancies, including breast, colorectal, lung, brain, pancreatic and urothelial cancers.
no Declined.[note 4]

___________
For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I sponsored by the National Cancer Institute, tipifarnib successfully passed phase I clinical trials but was suspended (NCT00029354) after phase II. Janssen investigated tipifarnib in patients 65 years of age and older with newly diagnosed acute myeloid leukemia (AML) and submitted a new drug application (NDA) to the FDA on January 24, 2005. In June 2005, the FDA issued a “not approvable” letter for tipifarnib.
 Already done.[note 5]

___________
Kura Oncology in-licensed tipifarnib from Janssen in 2014.
 Approved.Cite error: There are <ref> tags on this page without content in them (see the help page).

___________
and the former is currently investigating its therapeutic potential in select, genetically-defined patient populations.
no Declined.[note 6]

___________
The text to be deleted:-"patients 65 years of age and older with newly diagnosed acute myeloid leukemia (AML)." This is incorrect because it is outdated information.
no Declined.[note 7]

___________
"It inhibits the Ras kinase in a post-translational modification step before the kinase pathway becomes hyperactive. It inhibits prenylation of the CaaX tail motif, which allows Ras to bind to the membrane where it is active. Without this step the protein cannot function." I rephrased this in order to be more in line with the sources used.
 Unable to implement.[note 8]

___________
"It is also being tested in clinical trials in patients in certain stages of breast cancer.[2] It is also investigated as a treatment for multiple myeloma." Outdated information
no Declined.[note 9]

___________
"The compound was discovered by and is under investigation by Johnson & Johnson Pharmaceutical Research & Development, L.L.C, with registration number R115777."
 Incomplete request.[note 10]

___________

  1. ^ This part of the edit request proposal was declined because the article's page number was not provided with the reference.
  2. ^ Part of this section of the proposed text was approved. The given reference states that TFI's block the activity noted above and does not mention Tipifarnib by name. Irregardless of the fact that Tipifarnib would be considered a TFI, this wording should not single out that agent over others in this group, as the reference provided also does not do so.
  3. ^ The asked-for changes in this section of the edit request are already in the article. Please note: The only items in this sentence that are asked to be changed have not been highlighted by the COI editor as the parts which are requested to be removed. (See note #10 below.)
  4. ^ This part of the edit request proposal was declined because part of the information already exists in other parts of the article.
  5. ^ The asked-for changes in this section of the edit request are already in the article.
  6. ^ This part of the edit request proposal was declined because its reference is a primary source document rather than an evaluative, secondary source. (See WP:MEDRS.)
  7. ^ Outdated information is typically not removable. (See WP:OUTDATED.)
  8. ^ This portion of your request could not be implemented because where it states that "I rephrased this" it is not clear whether "this" refers to the statement as it exists here at this exact spot in the text or higher up in the text where it appears in the first request section.
  9. ^ Outdated information is typically not removable. (See WP:OUTDATED, also Note #7 above.)
  10. ^ The section of text which is desired to be removed is not highlighted here (e.g., "and is under investigation by"). As these five words are the only components requested to be removed, they should have been flagged as such. (See note #3 above.)

Some proposed changes to Tipifarnib, Part III

[edit]

In regards to the new changes to tipfarnib's page, I have two minor requests for changes to help maintain the accuracy and flow of the page:

Under "History," I propose adding "Kura Oncology in-licensed tipifarnib from Janssen in 2014" to the end of this section, below the paragraph where it notes the FDA issuing a not approvable letter for tipifarnib. This is so that the section reads chronologically, rather than jumping around from year to year.

I also want to propose removing the INN proposed trade name, Zarnestra, as this is the name Janssen gave tipifarnib, and Janssen no longer has rights to it given that they've out-licensed it to Kura Oncology. Perhaps this proposed trade name could be discussed in the "History" section, but with it being at the very top as a descriptor, it feels inaccurate.

Please let me know if there are issues with these two proposed changes to the page. Thank you! Laurenruthfish (talk) 22:59, 4 October 2018 (UTC)[reply]

Reply 24-OCT-2018

[edit]

  Edit request partially implemented  

  1. Green tickY The claim regarding the in-licensing was moved.
  2. Red XN Moving the Zarnestra claim to another part of the article—the History section as proposed, for example—would necessitate knowing when that term originally applied. As the claim regarding Zarnestra is not referenced, it cannot be determined with certainty when the claim applied.

Regards,  Spintendo  22:42, 24 October 2018 (UTC)[reply]

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