throbber
0022-5347/04/1712-0041/0
`THE JOURNAL OF UROLOGY®
`Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
`
`Vol. 171, S41–S44, February 2004
`Printed in U.S.A.
`DOI: 10.1097/01.ju.0000108100.53239.b7
`
`NOVEL THERAPEUTIC MOLECULAR TARGETS FOR PROSTATE
`CANCER: THE MTOR SIGNALING PATHWAY AND EPIDERMAL GROWTH
`FACTOR RECEPTOR
`
`ANTHONY W. TOLCHER*
`From the Director Clinical Research, Institute for Drug Development Cancer Therapy and Research Center, San Antonio, Texas
`
`ABSTRACT
`Purpose: The scientific rationale and existing evidence for the use of novel molecular targets in
`the chemoprevention of cancer are reviewed, with special attention to prostate cancer.
`Materials and Methods: A search for relevant literature on basic science and clinical trials was
`conducted using PubMed/MEDLINE.
`Results: The emergence of molecularly targeted therapies for advanced malignancies creates
`an important opportunity to examine these agents for the chemoprevention of prostate cancer.
`Two critical targets in the proliferation and malignant transformation of normal cells, the
`PI3/Akt signal transduction pathway and the epidermal growth factor receptor, are currently the
`focus of several novel investigational therapies that are in late stage phase II and phase III
`studies.
`Conclusions: Research to date supports consideration of these novel molecular targets as future
`agents in the chemoprevention of prostate cancer.
`KEY WORDS: rapamycin; receptor, epidermal factor; prostatic neoplasms
`
`Advances in molecular genetics have identified several
`pathways of cellular proliferation and diminished apoptosis
`that represent interesting molecular targets for future che-
`moprevention studies. A pragmatic approach, based at least
`in part on the long interval between drug discovery and drug
`approval for advanced disease and subsequent evaluation for
`prevention, would view the drugs most worthy of discussion
`being those that are already in late stage clinical studies for
`advance disease. As such, 2 important molecular targets that
`mediate cellular proliferation, the epidermal growth factor
`receptor and the PI3 (phosphatidylinositol-3) kinase/Akt
`pathway, and the classes of agents that target these path-
`ways and are in late stage clinical development are reviewed.
`
`THE MTOR SIGNALING PATHWAY IN CANCER
`The PI3K/Akt signal transduction pathway is an attractive
`target for chemoprevention drug development. The Akt/PI3
`kinase pathway mediates the proliferative signals of several
`ligands and transmembrane receptors including insulin-like
`growth factor, neuron growth factor, platelet derived growth
`factor and immune cytokines such as interleukin-6 and 8.1– 8
`Based on epidemiological evidence suggesting that insulin-
`like growth factors have a role in the proliferation and de-
`velopment of prostate cancer and on circumstantial evidence
`and emerging data that suggest that the inflammatory pro-
`cess may also contribute to prostate duct proliferation and
`malignant transformation, this pathway may be a strategic
`target for the abrogation or inhibition of malignant change.
`Aberrant proliferative signals from either over expression of
`the receptor or ligands, or inactivation within PTEN gene
`(phosphatase and tensin homolog deleted on chromosome 10)
`lead to increased cellular proliferative signals and dimin-
`ished apoptosis.
`The PI3 kinase pathway is regulated at least in part by
`functional PTEN. Inactivation of the PTEN gene has been
`documented with high frequency in a broad spectrum of
`malignancies, including prostate cancer, and results in un-
`regulated stimulation of the Akt/PI3 kinase pathway.9 –11
`
`* Financial interest and/or other relationship with AstraZeneca.
`
`Stimulation of Akt/PI3 kinase ultimately leads to translation
`of proteins critical for G2/S migration and synthesis of ribo-
`somal and growth related proteins.12 In addition to these
`proliferative signals, phosphorylation of pro-apoptotic mem-
`bers of the Bcl-2 family, notably BAD, is a downstream even
`secondary to activation of the Akt/PI3 kinase pathway,
`thereby diminishing apoptosis.
`PTEN mutations, or mutations within the 10q 23 region,
`occur in approximately 49% of prostate carcinomas.13 A surge
`in phosphorylated-Akt (activated) is found in prostate intra-
`epithelial neoplasia (PIN) compared to adjacent normal pros-
`tate epithelia.14 However, not all investigators have demon-
`strated conclusively that phospho-Akt expression is present
`in high frequency in PIN. In 1 pathological series using
`immunohistochemical staining only 10% of PIN specimens
`stained positive for activated Akt.15 In another tumor model
`system increased Akt expression closely demarcated cells
`that possess PTEN inactivation from adjacent normal cells.16
`Taken together, this evidence suggests that mutations
`within PTEN and increased activation of the PI3 kinase/Akt
`pathway may represent an attractive target for the chemo-
`prevention of prostate cancer.
`
`THE LONG ROAD TO THE DISCOVERY OF RAPAMYCIN
`The development of specific inhibitors of the PI3 kinase/
`Akt pathway date back to the 1960s when a Canadian expe-
`dition traveled to Easter Island (Rapa Nui) to gather plant
`and soil samples. These soil samples were initially examined
`by what is now Wyeth Laboratories and were found to have
`interesting biological properties, including immunosuppres-
`sive and anticancer effects. The active agent was identified
`and isolated by Wyeth from the streptomyces hydroscopicus
`and was named sirolimus.17 Unfortunately, due to corporate
`priorities the project was not fully developed for more than 10
`years. Because of the signal transduction inhibitory proper-
`ties observed with this agent, the immunosuppressive mech-
`anism of rapamycin (sirolimus) was first recognized in cells
`dependent on the interleukin-2 receptor.
`Sirolimus binds intracellularly to the immunophilin
`
`S41
`
`Par Pharm., Inc.
`Exhibit 1037
`Page 001
`
`

`

`S42
`
`NOVEL THERAPEUTIC MOLECULAR TARGETS FOR PROSTATE CANCER
`
`FK506 binding protein 12 (FKBP 12), and the resulting com-
`plex inhibits the protein kinase activity of mammalian target
`of rapamycin (mTOR). Inhibition of mTOR affects the activ-
`ity of 2 separate downstream pathways that control the
`translation of specific mRNAs required for cell cycle traverse
`from G1 to S phase. Inhibition of mTOR affects the activity of
`the 40S ribosomal protein S6 kinase (p70s6k) and function of
`the eukaryotic initiation factor 4E-binding protein-1 (4E-
`BP1), leading to growth arrest in the G1 phase of the cell
`cycle. Furthermore, rapamycin prevents cyclin dependent
`kinase activation, inhibits retinoblastoma protein phosphor-
`ylation, and accelerates the turnover of cyclin D1 that leads
`to deficiency of the active cdk4/cyclin D1 complexes, all of
`which inhibit G1/S traverse.17 In 1987 research into siroli-
`mus was resurrected following the merger of Wyeth and
`Ayerst, and was developed as an immunosuppressant agent.
`Concurrently, the role of Akt/PI3 kinase pathway and mTOR
`in the growth and proliferation of cancer cells was further
`delineated and this agent was selected for anticancer devel-
`opment. Noteworthy, preclinical data indicate that PTEN
`null cells have enhanced sensitivity to mTOR inhibition in
`vivo.18
`In addition to the antiproliferative effects on malignant
`cells, antiangiogenic properties were associated with this
`class of compounds as first described by Guba et al.19 Rapa-
`mycin leads to inhibition of endothelial cell proliferation and
`decreased vascular endothelial growth factor expression. The
`impact of the antiproliferative effects on malignant cells and
`the anti-invasive and antiangiogenic effects appear to vary
`with dose and schedules.19
`There are several mTOR inhibitors in clinical development
`for cancer therapy. CCI-779 is a rapamycin derivative devel-
`oped by Wyeth-Ayerst which has completed phase I studies
`as a single agent using intravenous formulation and oral
`formulation. It is currently in combination studies with other
`anticancer agents and in a broad spectrum of phase II single
`agent studies. A testament to the interest in this class of
`compounds, several analogues are currently being clinically
`developed by large and small pharma.
`The first clinical trials of patients with CCI-779 were per-
`formed in the United States and Europe. The daily times 5
`intravenous schedule was used at The Cancer Therapy and
`Research Center in San Antonio along with the Mayo Clinic,
`whereas the weekly schedule of intravenous rapamycin was
`used in Europe. Remarkably, antitumor activity was seen
`across a broad spectrum of doses. Notable in the phase I
`studies were bonafide partial responses seen in renal cell
`carcinoma, nonsmall cell lung cancer, breast cancer and a
`neuroendocrine tumor. The toxicity observed is considered
`moderate in relation to other anticancer agents. This agent
`also has an extensive safety database from organ transplan-
`tation cases and the use of rapamycin coated stents for the
`prevention of coronary artery stenosis.
`No nausea or vomiting was seen and, therefore, no premed-
`ication was required. Opportunistic infections were not ob-
`served in either of the phase I studies. There was only a
`modest amount of hematological toxicity noted at most dose
`levels. Some central nervous system effects, including exci-
`tation and depression, were noted at high doses, and testos-
`terone levels decreased in some male patients. In addition,
`skin toxicity was commonly observed and described as small
`erythematous papules and folliculitis observed on the trunk
`and face of some patients, as well splitting at the base of nail
`was. In the weekly study a maximum tolerated dose was not
`determined. Doses of 7.5 to 220 mg/m2 could be administered
`weekly without dose limiting toxicity and without exceeding
`the threshold for dose limiting toxicity. In the United States
`study 15 mg/m2 administered daily for 5 days was adminis-
`tered safely in patients who were heavily pretreated,
`whereas 24 mg/m2 intravenously daily times 5 days could be
`administered to patients who were minimally pretreated.
`
`Dose limiting toxicity included grade 3 elevation of liver
`function abnormalities at 19.1 mg/m2 and grade 3 hypocal-
`cemia. There was no obvious relationship between dose and
`observed activity with tumor regression observed across the
`entire spectrum of doses.20
`
`RAPAMYCIN ANALOGUES AS POTENTIAL CHEMOPREVENTIVE
`AGENTS
`Rapamycin analogues are attractive chemoprevention
`agents. They are orally bioavailable, have an established
`toxicity profile culled from many years of use in the trans-
`plantation setting, are active compounds leading to apoptosis
`and tumor regression in advanced disease, and target a crit-
`ical signal transduction pathway used in many malignancies.
`The clinical development of targeted therapies has created
`new challenges for the interpretation of efficacy and success-
`ful drug approval. The template for most oncology registra-
`tion strategies has been tumor site specific, irrespective of
`the molecular heterogeneity that ultimately leads to malig-
`nant transformation. This design has also been applied to the
`limited number of prevention studies performed to date, in-
`cluding tamoxifen for breast cancer prevention and finas-
`teride for prostate cancer prevention. However, it is probable
`that with rapamycin, an agent that specifically targets tumor
`growth mediated by dysregulated activation of Akt/PI3 ki-
`nase pathway, will have activity only in cells in which this
`pathway is critical for malignant transformation and prolif-
`eration. Therefore, the rational clinical development of this
`drug for chemoprevention may be limited to patients who are
`at high risk for prostate cancer and who demonstrate evi-
`dence of PTEN inactivation or increased Akt activation in
`prostate or PIN cells detected at biopsy. This niche market
`may represent an opportunity for rational chemoprevention
`but also a potential limitation to future market size—an
`issue critical to the acceptance of chemoprevention agents as
`viable “products” by manufacturers.
`
`THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AS A
`TARGET FOR CHEMOPREVENTION
`EGFR over expression and the ligand transforming growth
`factor-␣ have been identified in pathological specimens con-
`taining high grade prostatic intraepithelial hyperplasia,
`whereas less frequent and lower expression has been noted in
`low grade PIN and normal prostatic epithelia.21–23 Further-
`more, tumor transforming growth factor-␣ expression is in-
`creased in specimens containing PIN, a coexisting carcinoma,
`suggesting a role in the proliferation of early transformed
`prostate epithelia.21 EGFR is a member of a family of erbB
`receptors and ligands. ErbB2 or Her2/neu is the prototypic
`member of this family associated with poor prognosis in
`breast cancer, and is the target for the first successful devel-
`opment of a molecularly targeted agent in solid tumor oncol-
`ogy (trastuzumab). Other EGFR family members, erbB3 and
`erbB4, do not have a defined role in the transformation and
`proliferation of prostate cancer. Members of the erbB recep-
`tor
`family
`undergo
`homo-dimerization
`and
`hetero-
`dimerization in response to relevant ligand binding, result-
`ing in tyrosine kinase activity at the intracellular receptor
`domain, phosphorylation and signaling of the MAP kinase
`pathway.24
`There are several EGFR targeting therapies in clinical
`development. Monoclonal antibodies, chimeric (Imclone
`C225) and human (Abgenix EGF), are currently in late phase
`III clinical development for advanced solid tumors including
`colorectal and nonsmall cell lung cancer. Small molecule
`tyrosine kinase inhibitors, such as ZD1839 and OSI-774, are
`also in late stage clinical studies, with ZD1839 pending reg-
`ulatory approval for the treatment of nonsmall cell lung
`cancer.25 Characteristic toxicities associated with monoclo-
`nal antibodies include an acneiform rash that forms on the
`
`Par Pharm., Inc.
`Exhibit 1037
`Page 002
`
`

`

`NOVEL THERAPEUTIC MOLECULAR TARGETS FOR PROSTATE CANCER
`
`S43
`
`upper body and face that is dose dependent, which is consis-
`tent with folliculitis and is treated with topical steroids and
`minocycline.
`Albeit infrequent, hypersensitivity reactions are associ-
`ated with use of the chimeric monoclonal antibody C225.26, 27
`ZD1839 and OSI-774 have elimination half-lives that approx-
`imate 24 hours and are administered once daily. Toxicity
`profiles associated with small tyrosine kinase inhibitors is
`similar, although, in addition to the acneiform rash, diarrhea
`is dose-limiting. Diarrhea is manageable with the use of
`simple antidiarrheal agents such as imodium. In contrast to
`the small molecule tyrosine kinase inhibitors in which daily
`dosing is appropriate, the monoclonal antibodies all have
`relatively long elimination half-lives that extend from 10 to
`20 days and can be administered weekly or potentially long-
`er.25 All of these agents have demonstrated single agent
`antitumor activity.28
`Abnormal growth factor receptor targeting agents may be
`attractive for chemoprevention studies. Two or three agents
`may be approved in the next 2 to 3 years, including C225,
`Abgenix EGF antibody and Iressa. Based on intriguing evi-
`dence that EGFR is over expressed in PIN, the good tolera-
`bility profile of these agents in chronic dosing schedules, and
`evidence of apoptosis induction and regression of tumors that
`EGFR expression is critical for cell proliferation and survival,
`the selection of these agents for chemoprevention studies
`represents a rational “next step”. The identification of the
`appropriate subgroups at high risk for prostate cancer and in
`which EGFR expression is a pivotal driving molecular path-
`way remains an important challenge for this class of molec-
`ularly targeted agents.
`
`CONCLUSIONS
`Although several molecular targets are attractive for che-
`moprevention, those pathways with late stage clinical devel-
`opment represent the most practical agents to consider for
`prevention studies. These include agents that target EGFR
`and mTOR signaling pathways, which are associated with
`modest toxicities in phase I and phase II studies, can be
`administered for prolonged periods to patients and, there-
`fore, are well suited to chemoprevention strategies. The key
`to these molecularly targeted agents will be identification of
`predictive biomarkers so that appropriate patients are se-
`lected as candidates for studies to determine the efficacy of
`these agents.
`
`REFERENCES
`1. Debes, J. D., Schmidt, L. J., Huang, H. and Tindall, D. J.: P300
`mediates androgen-independent transactivation of the andro-
`gen receptor by interleukin 6. Cancer Res, 62: 5632, 2002
`2. Heber, D. and Lu, Q. Y.: Overview of mechanisms of action of
`lycopene. Exp Biol Med, 227: 920, 2002
`3. Mercader, M., Bodner, B. K., Moser, M. T., Kwon, P. S., Park,
`E. S., Manecke, R. G. et al: T cell infiltration of the prostate
`induced by androgen withdrawal in patients with prostate
`cancer. Proc Natl Acad Sci USA, 98: 14565, 2001
`4. Nelson, W. G., DeWeese, T. L. and DeMarzo, A. M.: The diet,
`prostate inflammation, and the development of prostate can-
`cer. Cancer Metastasis Rev, 21: 3, 2002
`5. Twillie, D. A., Eisenberger, M. A., Carducci, M. A., Hseih, W. S.,
`Kim, W. Y. and Simons, J. W.: Interleukin-6: a candidate
`mediator of human prostate cancer morbidity. Urology, 45:
`542, 1995
`6. Burroughs, K. D., Oh, J., Barrett, J. C. and DiAugustine, R. P.:
`Phosphatidylinositol 3-kinase and mek1/2 are necessary for
`insulin-like growth factor-I-induced vascular endothelial
`growth factor synthesis in prostate epithelial cells: a role for
`hypoxia-inducible factor-1? Mol Cancer Res, 1: 312, 2003
`7. Chan, J. M., Stampfer, M. J., Giovannucci, E., Gann, P. H., Ma,
`J., Wilkinson, P. et al: Plasma insulin-like growth factor-I and
`prostate cancer risk: a prospective study. Science, 279: 563,
`1998
`
`8. Signorello, L. B., Brismar, K., Bergstrom, R., Andersson, S. O.,
`Wolk, A., Trichopoulos, D. et al: Insulin-like growth factor-
`binding protein-1 and prostate cancer. J Natl Cancer Inst, 91:
`1965, 1999
`9. Whang, Y. E., Wu, X., Suzuki, H., Reiter, R. E., Tran, C.,
`Vessella, R. L. et al: Inactivation of the tumor suppressor
`PTEN/MMAC1 in advanced human prostate cancer through
`loss of expression. Proc Natl Acad Sci USA, 95: 5246, 1998
`10. Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S. I. et
`al: PTEN, a putative protein tyrosine phosphatase gene mu-
`tated in human brain, breast, and prostate cancer. Science,
`275: 1943, 1997
`11. McMenamin, M. E., Soung, P., Perera, S., Kaplan, I., Loda, M.
`and Sellers, W. R.: Loss of PTEN expression in paraffin-
`embedded primary prostate cancer correlates with high Gleason
`score and advanced stage. Cancer Res, 59: 4291, 1999
`12. Vivanco, I. and Sawyers, C. L.: The phosphatidylinositol
`3-Kinase AKT pathway in human cancer. Nat Rev Cancer, 2:
`489, 2002
`13. Feilotter, H. E., Nagai, M. A., Boag, A. H., Eng, C. and Mulligan,
`L. M.: Analysis of PTEN and the 10q23 region in primary
`prostate carcinomas. Oncogene, 16: 1743, 1998
`14. Paweletz, C. P., Charboneau, L., Bichsel, V. E., Simone, N. L.,
`Chen, T., Gillespie, J. W. et al: Reverse phase protein microar-
`rays which capture disease progression show activation of
`pro-survival pathways at the cancer invasion front. Oncogene,
`20: 1981, 2001
`15. Malik, S. N., Brattain, M., Ghosh, P. M., Troyer, D. A., Prihoda,
`T., Bedolla, R. et al: Immunohistochemical demonstration of
`phospho-Akt in high Gleason grade prostate cancer. Clin Can-
`cer Res, 8: 1168, 2002
`16. Kwabi-Addo, B., Giri, D., Schmidt, K., Podsypanina, K., Parsons,
`R., Greenberg, N. et al: Haploinsufficiency of the Pten tumor
`suppressor gene promotes prostate cancer progression. Proc
`Natl Acad Sci USA, 98: 11563, 2001
`17. Hidalgo, M. and Rowinsky, E. K.: The rapamycin-sensitive sig-
`nal transduction pathway as a target for cancer therapy. On-
`cogene, 19: 6680, 2000
`18. Neshat, M. S., Mellinghoff, I. K., Tran, C., Stiles, B., Thomas, G.,
`Petersen, R. et al: Enhanced sensitivity of PTEN-deficient
`tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA,
`98: 10314, 2001
`19. Guba, M., von Breitenbuch, P., Steinbauer, M., Koehl, G., Flegel,
`S., Hornung, M. et al: Rapamycin inhibits primary and meta-
`static tumor growth by antiangiogenesis: involvement of vas-
`cular endothelial growth factor. Nat Med, 8: 128, 2002
`20. Dancey, J. E.: Clinical development of mammalian target of
`rapamycin inhibitors. Hematol Oncol Clin North Am, 16:
`1101, 2002
`21. Harper, M. E., Glynne-Jones, E., Goddard, L., Mathews, P. and
`Nicholson, R. I.: Expression of androgen receptor and growth
`factors in premalignant lesions of the prostate. J Pathol, 186:
`169, 1998
`22. Leav, I., McNeal, J. E., Ziar, J. and Alroy, J.: The localization of
`transforming growth factor alpha and epidermal growth factor
`receptor in stromal and epithelial compartments of developing
`human prostate and hyperplastic, dysplastic, and carcinoma-
`tous lesions. Hum Pathol, 29: 668, 1998
`23. Scher, H. I., Sarkis, A., Reuter, V., Cohen, D., Netto, G.,
`Petrylak, D. et al: Changing pattern of expression of the epi-
`dermal growth factor receptor and transforming growth factor
`alpha in the progression of prostatic neoplasms. Clin Cancer
`Res, 1: 545, 1995
`24. Hackel, P. O., Zwick, E., Prenzel, N. and Ullrich, A.: Epidermal
`growth factor receptors: critical mediators of multiple receptor
`pathways. Curr Opin Cell Biol, 11: 184, 1999
`25. Mendelsohn, J.: Targeting the epidermal growth factor receptor
`for cancer therapy. J Clin Oncol, suppl., 20: 1S, 2002
`26. Needle, M. N.: Safety experience with IMC-C225, an anti-
`epidermal growth factor receptor antibody. Semin Oncol,
`suppl., 29: 55, 2002
`27. Kies, M. S. and Harari, P. M.: Cetuximab (Imclone/Merck/
`Bristol-Myers Squibb). Curr Opin Investig Drugs, 3: 1092,
`2002
`28. de Bono, J. S. and Rowinsky, E. K.: The ErbB receptor family: a
`therapeutic target for cancer. Trends Mol Med, suppl. 8: S19,
`2002
`
`Par Pharm., Inc.
`Exhibit 1037
`Page 003
`
`

`

`S44
`
`NOVEL THERAPEUTIC MOLECULAR TARGETS FOR PROSTATE CANCER
`
`DISCUSSION
`
`Dr. Ian M. Thompson. When we consider chemoprevention, we think about giving the patient an agent on a
`daily basis. If we really believe that premalignant intraepithelial lesions ultimately invade, I wonder whether we
`could possibly pulse some of these agents, allowing the patient to shed the so-called “bad” epithelial cells. The
`kinds of agents you described, especially those with long half-lives, might be very amenable to this approach.
`Dr. Anthony W. Tolcher. One of the nice things about some of the antibodies is that they have a tremendously
`long half-life. HER-2 over expression is found commonly in carcinoma in situ of the breast. The question is can
`one target that with an antibody such as herceptin or an anti-EGFR antibody, which has an elimination half-life
`of 21 days, potentially allowing monthly administration for 6 months followed by 3 additional months of
`coverage. That may be all that is necessary. If the cells are dependent on that pathway for proliferation or cell
`survival, once you take away that cell proliferative pathway, the cells will undergo apoptosis, which clearly does
`occur in certain dependent cells. You would actually have a brief period of intervention instead of lifelong drug
`therapy.
`Dr. Leslie G. Ford. The rash is clearly a limiting factor. Is it dose dependent or are some people just reactors?
`Doctor Tolcher. The rash is certainly dose dependent. Currently, we actually like to see the rash because we
`are still testing toxicity. In the model we use for the cytotoxic therapy, if you do not see decreasing blood counts,
`you think you are not giving enough chemotherapy.
`Doctor Ford. Given the redundancy, when you block 1 part of the pathway or hit 1 target, everything just finds
`another pathway. Is it realistic to think you could give a single agent?
`Doctor Tolcher. I will tell you why I think so. Although I agree that there is redundancy, I think that we
`sometimes become too negative. We take it for granted that it will just be compensated but patients actually have
`tumor regression with some of these agents, thereby demonstrating critical reliance on 1 single pathway for some
`cells.
`Doctor Ford. But it isn’t disappearance; the tumor regresses and then comes back at some point.
`Doctor Tolcher. The multitargeted, multistep process of malignancy may be such that when we are targeting
`it at its earliest form, we are actually looking for 1 or 2 mutations and not 7 or 8. We are not looking at redundant
`systems that are already in place.
`Doctor Ford. Some of the agents being developed for treatment should actually be developed for prevention.
`However, it is difficult to get a pharmaceutical firm to think that way.
`Dr. Neil Fleshner. Given that prevention is such a long business and patent lives are shorter than that, unless
`we have an intermediate end point, how will any pharmaceutical company invest in prevention in the real world?
`There may be agents that have no efficacy in end stage disease or in established disease, but may be useful as
`preventive agents, and we will never see them developed.
`Doctor Tolcher. We have to change the way we develop and approve drugs. You currently see advertisements
`promoting an analogue of sirolimus as a nonsteroidal cream for eczema. It is interesting that we can get access
`to a drug like that to treat eczema but cannot get a drug like sirolimus approved for oncology. Currently,
`sirolimus is only approved for transplants.
`
`Par Pharm., Inc.
`Exhibit 1037
`Page 004
`
`

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket