0022-5347/04/1712-0041/0
`THE JOURNAL OF URoLocy®
`Copyright © 2004 by American URoLocicaL ASSOCIATION
`
`Vol. 171, 841-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
`
`From the Director Clinical Research, Institute for Drug Development Cancer Therapy and Research Center, San Antonio, Texas
`
`ANTHONY W. TOLCHER*
`
`ABSTRACT
`
`Purpose: Thescientific rationale and existing evidencefor the use of novel molecular targets in
`the chemoprevention of cancer are reviewed, with special attention to prostate cancer.
`Materials and Methods:A searchfor relevant literature on basic science andclinical 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 growthfactor receptor, are currently the
`focus of several novel investigational therapies that are in late stage phase II and phaseIII
`studies.
`Conclusions: Research to date supports consideration ofthese novel molecular targets as future
`agents in the chemoprevention of prostate cancer.
`Key WorbDs: rapamycin; receptor, epidermal factor; prostatic neoplasms
`
`Advances in molecular genetics have identified several
`pathwaysof 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
`mediatecellular proliferation, the epidermal growth factor
`receptor and the PI3 (phosphatidylinositol-3) kinase/Akt
`pathway, andthe classes of agents that target these path-
`ways andarein late stage clinical development are reviewed.
`
`THE MTOR SIGNALING PATHWAY IN CANCER
`
`The PI3K/Akt signal transduction pathwayis an attractive
`target for chemoprevention drug development. The Akt/PI3
`kinase pathway mediates the proliferative signals of several
`ligands and transmembranereceptors including insulin-like
`growth factor, neuron growth factor, platelet derived growth
`factor and immunecytokinessuch 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.
`Aberrantproliferative signals from either over expression of
`the receptor or ligands, or inactivation within PTEN gene
`(phosphatase and tensin homolog deleted on chromosome10)
`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.9-1
`
`* Financial interest and/or other relationship with AstraZeneca.
`
`Stimulation of Akt/PI3 kinase ultimately leads to translation
`of proteins critical for G,/S migration and synthesis of ribo-
`somal and growth related proteins.!2 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 mayrepresent 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 namedsirolimus.’ 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) wasfirst recognized in cells
`dependenton the interleukin-2 receptor.
`Sirolimus binds
`intracellularly to the immunophilin
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`NOVEL THERAPEUTIC MOLECULAR TARGETS FOR PROSTATE CANCER
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`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 requiredfor cell cycle traverse
`from G1 to S phase. Inhibition of mTORaffects 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 ofthe cell
`cycle. Furthermore, rapamycin prevents cyclin dependent
`kinase activation, inhibits retinoblastoma protein phosphor-
`ylation, and accelerates the turnoverof cyclin D1 that leads
`to deficiency of the active cdk4/cyclin D1 complexes,all of
`which inhibit G1/S traverse.!” 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 andproliferation 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 compoundsasfirst described by Guba et al.19 Rapa-
`mycin leadsto 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
`Thereare several mTORinhibitorsin clinical development
`for cancer therapy. CCI-779 is a rapamycin derivative devel-
`oped by Wyeth-Ayerst which has completed phaseI 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 phaseII single
`agent studies. A testament to the interest in this class of
`compounds, several analogues are currently beingclinically
`developed by large and small pharma.
`Thefirst 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 nauseaor 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 malepatients. In addition,
`skin toxicity was commonly observed and described as small
`erythematous papules and folliculitis observed on the trunk
`and face of somepatients, as well splitting at the baseofnail
`was. In the weekly study a maximum tolerated dose was not
`determined. Doses of 7.5 to 220 mg/m? could be administered
`weekly without dose limiting toxicity and without exceeding
`the threshold for dose limiting toxicity. In the United States
`study 15 mg/m? administered daily for 5 days was adminis-
`tered safely in patients who were heavily pretreated,
`whereas 24 mg/m” 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/m? and grade 3 hypocal-
`cemia. There was no obviousrelationship between dose and
`observedactivity with tumor regression observed across the
`entire spectrum of doses.2°
`
`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 compoundsleadingto apoptosis
`and tumorregression in advanced disease, and targeta crit-
`ical signal] transduction pathway used in many malignancies.
`The clinical development of targeted therapies has created
`new challengesfor the interpretation of efficacy and success-
`ful drug approval. The template for most oncology registra-
`tion strategies has been tumorsite specific, irrespective of
`the molecular heterogeneity that ultimately leads to malig-
`nant transformation. This design has also been applied to the
`limited numberof 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
`pathwayis critical for malignant transformation and prolif-
`eration. Therefore, the rational clinical developmentof this
`drug for chemoprevention maybe 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
`issuecritical to the acceptance of chemoprevention agents as
`viable “products” by manufacturers.
`
`THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AS A
`TARGET FOR CHEMOPREVENTION
`
`EGFRover expression and the ligand transforming growth
`factor-a have been identified in pathological specimens con-
`taining high grade prostatic intraepithelial hyperplasia,
`whereasless frequent and lower expression has been noted in
`low grade PIN and normal prostatic epithelia.21-23 Further-
`more, tumor transforming growth factor-a 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 memberof 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, andis the target for the first successful devel-
`opmentof a molecularly targeted agent in solid tumoroncol-
`ogy (trastuzumab). Other EGFR family members, erbB3 and
`erbB4, do not have a definedrole 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.?4
`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.?5 Characteristic toxicities associated with monoclo-
`nal antibodies include an acneiform rash that forms on the
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`NOVEL THERAPEUTIC MOLECULAR TARGETS FOR PROSTATE CANCER
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`543
`
`upper body and face that is dose dependent, whichis 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 haveelimination 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
`antitumoractivity.2®
`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 EGFRis over expressed in PIN, the goodtolera-
`bility profile of these agents in chronic dosing schedules, and
`evidenceof apoptosis induction and regression of tumors that
`EGFRexpressioniscritical for cell proliferation and survival,
`the selection of these agents for chemoprevention studies
`represents a rational “next step”. The identification of the
`appropriate subgroupsat 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 mTORsignaling 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 determinethe efficacy of
`these agents.
`
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`DISCUSSION
`
`Dr. Ian M. Thompson. When weconsider 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 someof 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 someof the antibodies is that they have a tremendously
`long half-life. HER-2 over expression is found commonly in carcinomain 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 maybeall that is necessary. If the cells are dependent on that pathwayfor proliferation or cell
`survival, once you take awaythatcell proliferative pathway, the cells will undergo apoptosis, which clearly does
`occur in certain dependentcells. You would actually have a brief period of intervention instead oflifelong drug
`therapy.
`Dr. Leslie G. Ford. The rashis clearly a limiting factor. Is it dose dependent or are somepeople 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 weuse 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 youblock 1 part of the pathwayor 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. Wetakeit for granted thatit will just be compensated but patients actually have
`tumorregression with someof 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 somepoint.
`Doctor Tolcher. The multitargeted, multistep process of malignancy may be such that when weare targeting
`it at its earliest form, we are actually looking for 1 or 2 mutations andnot7 or 8. We are not looking at redundant
`systems that are already in place.
`Doctor Ford. Someof 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 patentlives are shorter than that, unless
`we havean intermediate end point, how will any pharmaceutical companyinvest in prevention in the real world?
`There may be agents that havenoefficacy 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 analogueof 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.
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