Pathology in drug discovery and development
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Journal of Pathology J Pathol 2014; 232: 99–102 Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/path.4290 INTRODUCTORY ARTICLE Pathology in drug discovery and development # Adrian M Jubb, 1 * Hartmut Koeppen 2 and Jorge S Reis-Filho 3 1 Department of Product Development – Oncology, Genentech Inc., South San Francisco, CA, USA 2 Department of Pathology, Genentech Inc., South San Francisco, CA, USA 3 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA *Correspondence to: A M Jubb, Department of Product Development – Oncology, Genentech Inc., South San Francisco, CA, USA. e-mail: [email protected] # The views expressed herein are those of the authors alone and do not necessarily reflect the views of their respective institutions or employers. Abstract The rapid pace of drug discovery and drug development in oncology, immunology and ophthalmology brings new challenges; the efficient and effective development of new targeted drugs will require more detailed molecular classifications of histologically homogeneous diseases that show heterogeneous clinical outcomes. To this end, single companion diagnostics for specific drugs will be replaced by multiplex diagnostics for entire therapeutic areas, preserving tissue and enabling rapid molecular taxonomy. The field will move away from the development of new molecular entities as single agents, to which resistance is common. Instead, a detailed understanding of the pathological mechanisms of resistance, in patients and in preclinical models, will be key to the validation of scientifically rational and clinically effective drug combinations. To remain at the heart of disease diagnosis and appropriate management, pathologists must evolve into translational biologists and biomarker scientists. Herein, we provide examples of where this metamorphosis has already taken place, in lung cancer and melanoma, where the transformation has yet to begin, in the use of immunotherapies for ophthalmology and oncology, and where there is fertile soil for a revolution in treatment, in efforts to classify glioblastoma and personalize treatment. The challenges of disease heterogeneity, the regulatory environment and adequate tissue are ever present, but these too are being overcome in dedicated academic centres. In summary, the tools necessary to overcome the ’whens’ and ’ifs’ of the molecular revolution are in the hands of pathologists today; it is a matter of standardization, training and leadership to bring these into routine practice and translate science into patient benefit. This Annual Review Issue of the Journal of Pathology highlights the central role for pathology in modern drug discovery and development. Copyright 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Keywords: pathology; drug development; companion diagnostics; biomarkers Received 30 September 2013; Revised 30 September 2013; Accepted 1 October 2013 Conflicts of interest: Dr Hartmut Koeppen and Dr Adrian Jubb are employees of, and hold equity in, Genentech/Roche. Despite the advances seen with targeted therapies and immunotherapies in cancer and other diseases, cures are elusive, the process inefficient (with few can- didates becoming approved drugs) and development costs remain high. Moreover, the time taken to evaluate and approve even promising therapies is long. Appro- priate anatomical, molecular and chemical pathology could significantly improve this process by helping to select the right patient population, identify new sur- rogate endpoints and determine mechanisms of drug resistance. This 2014 Annual Review Issue highlights the central and expanding role for pathology in all stages of drug discovery and development. In pre- clinical research and development, pathology is vital to validate models of disease that can inform dis- ease biology and be used to evaluate drug candi- dates [1,2]. For example, the demonstration of invasive lung adenocarcinomas in mice genetically engineered to express the EML4–ALK fusion gene was key to defining ALK as a driver oncogene in NSCLC [3,4]. Careful pathological assessment is essential to confirm and characterize the prevalence of putative drug tar- gets [5,6], defining the size of the unmet medical need and optimizing clinical trial design to identify those most likely to benefit. Finally, pathological assessment is critical to evaluate the potential toxicity of a given agent in model systems; histopathology illustrated the potential for BRAF -V600 inhibitors to promote hyper- plasia in normal epidermis, a prelude to the keratoacan- othomas seen with vemurafenib and dabrafenib [7,8]. In clinical development, pathology is important for the correct interpretation and attribution of adverse events. Histopathology is a key tool in the evaluation of pharmacodynamic biomarkers [9]; for example, the Copyright 2013 Pathological Society of Great Britain and Ireland. J Pathol 2014; 232: 99–102 Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk www.thejournalofpathology.com
Transcript of Pathology in drug discovery and development
Journal of PathologyJ Pathol 2014; 232: 99–102Published online in Wiley Online Library(wileyonlinelibrary.com) DOI: 10.1002/path.4290
INTRODUCTORY ARTICLE
Pathology in drug discovery and development#
Adrian M Jubb,1* Hartmut Koeppen2 and Jorge S Reis-Filho3
1 Department of Product Development – Oncology, Genentech Inc., South San Francisco, CA, USA2 Department of Pathology, Genentech Inc., South San Francisco, CA, USA3 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
*Correspondence to: A M Jubb, Department of Product Development – Oncology, Genentech Inc., South San Francisco, CA, USA. e-mail:[email protected]
#The views expressed herein are those of the authors alone and do not necessarily reflect the views of their respective institutions oremployers.
AbstractThe rapid pace of drug discovery and drug development in oncology, immunology and ophthalmology brings newchallenges; the efficient and effective development of new targeted drugs will require more detailed molecularclassifications of histologically homogeneous diseases that show heterogeneous clinical outcomes. To this end,single companion diagnostics for specific drugs will be replaced by multiplex diagnostics for entire therapeuticareas, preserving tissue and enabling rapid molecular taxonomy. The field will move away from the developmentof new molecular entities as single agents, to which resistance is common. Instead, a detailed understanding ofthe pathological mechanisms of resistance, in patients and in preclinical models, will be key to the validation ofscientifically rational and clinically effective drug combinations. To remain at the heart of disease diagnosis andappropriate management, pathologists must evolve into translational biologists and biomarker scientists. Herein,we provide examples of where this metamorphosis has already taken place, in lung cancer and melanoma, wherethe transformation has yet to begin, in the use of immunotherapies for ophthalmology and oncology, and wherethere is fertile soil for a revolution in treatment, in efforts to classify glioblastoma and personalize treatment. Thechallenges of disease heterogeneity, the regulatory environment and adequate tissue are ever present, but thesetoo are being overcome in dedicated academic centres. In summary, the tools necessary to overcome the ’whens’and ’ifs’ of the molecular revolution are in the hands of pathologists today; it is a matter of standardization,training and leadership to bring these into routine practice and translate science into patient benefit. This AnnualReview Issue of the Journal of Pathology highlights the central role for pathology in modern drug discovery anddevelopment.Copyright 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Keywords: pathology; drug development; companion diagnostics; biomarkers
Received 30 September 2013; Revised 30 September 2013; Accepted 1 October 2013
Conflicts of interest: Dr Hartmut Koeppen and Dr Adrian Jubb are employees of, and hold equity in, Genentech/Roche.
Despite the advances seen with targeted therapies andimmunotherapies in cancer and other diseases, curesare elusive, the process inefficient (with few can-didates becoming approved drugs) and developmentcosts remain high. Moreover, the time taken to evaluateand approve even promising therapies is long. Appro-priate anatomical, molecular and chemical pathologycould significantly improve this process by helping toselect the right patient population, identify new sur-rogate endpoints and determine mechanisms of drugresistance. This 2014 Annual Review Issue highlightsthe central and expanding role for pathology in allstages of drug discovery and development. In pre-clinical research and development, pathology is vitalto validate models of disease that can inform dis-ease biology and be used to evaluate drug candi-dates [1,2]. For example, the demonstration of invasive
lung adenocarcinomas in mice genetically engineeredto express the EML4–ALK fusion gene was key todefining ALK as a driver oncogene in NSCLC [3,4].Careful pathological assessment is essential to confirmand characterize the prevalence of putative drug tar-gets [5,6], defining the size of the unmet medical needand optimizing clinical trial design to identify thosemost likely to benefit. Finally, pathological assessmentis critical to evaluate the potential toxicity of a givenagent in model systems; histopathology illustrated thepotential for BRAF -V600 inhibitors to promote hyper-plasia in normal epidermis, a prelude to the keratoacan-othomas seen with vemurafenib and dabrafenib [7,8].In clinical development, pathology is important for thecorrect interpretation and attribution of adverse events.
Histopathology is a key tool in the evaluation ofpharmacodynamic biomarkers [9]; for example, the
Copyright 2013 Pathological Society of Great Britain and Ireland. J Pathol 2014; 232: 99–102Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk www.thejournalofpathology.com
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use of human tissue to evaluate phospho-ERK statuswas able to provide early pharmacodynamic evidencethat BRAF -V600 inhibitors were achieving the desiredbiological effect at tolerable doses [10]. The correctdefinition of the patient population under study, includ-ing diagnosis, staging and biomarker status, is vital fora positive trial [9]. Understanding that pemetrexed isonly effective in adenocarcinomas [11] and that beva-cizumab shows potential toxicity in squamous cell car-cinomas was key to the demonstration of favourablebenefit–risk profiles for both drugs [12]. The successfuldevelopment of MET inhibitors (such as onartuzumaband rilotumumab) in lung and gastric cancer is depen-dent on the co-development of companion diagnosticsthat can identify populations most likely to benefit[5]. Moreover, the regulatory acceptability of key end-points, such as complete pathological response, relieson the rigor of the pathologist [9,13,14]. In particu-lar, understanding and controlling pre-analytical andanalytical pathological variables, such as the tissuesampling, fixative and storage of the specimen, areimportant for the regulatory approval of a companiondiagnostic and for its successful implementation in theclinic [15,16]. Despite this central role for pathology inthe discovery, development and approval of new drugs,there is significant untapped potential for pathology tobring forward new breakthrough therapies (Table 1).
Cross-pollination between traditionally segregatedtherapeutic areas is forcing pathologists to collaboratewithin their discipline and with other clinical special-ties and research groups. For instance, anti-VEGF ther-apies first demonstrated promise as anti-cancer agents,but later were shown to improve the vision of patientswith wet age-related macular degeneration (AMD) anddiabetic macular oedema [17]. The last few years haveseen promising early data for a new generation ofimmunotherapy drugs (eg anti-PD1/PDL1 and/or anti-CTLA4 therapies) in lung cancer [18,19], melanoma[7,18–21] and renal cell carcinoma [18,19]. Yet not allpatients may benefit from immunotherapy; the use andfurther development of these agents will depend on agreater understanding of biomarkers of the anti-tumourimmune response, an area neglected in the traditionallycancer cell-centric field of companion diagnostics [22].Similarly, tackling dry AMD may also rely heavily ontargeting complement and immune cells [17]. Thus, agreater understanding of immunology and immunother-apies is becoming essential to pathologists working ina wide variety of disciplines.
While histopathology is still relevant to the diagno-sis of disease, the shift from histological to molecularclassifications of disease is accelerating. The treat-ment of advanced NSCLC and melanoma by targetingdriver oncogenes within the practice of medicine isbecoming the standard of care in many key academiccentres [3,7]. It is clear that HER-targeted therapiesrely on companion diagnostics to predict early bene-fit and biomarkers can predict eventual resistance [23].Breast carcinoma has long been classified in molecu-lar terms, which define treatment and outcome, but the
further sub-classification of triple-negative breast can-cer is seen as key to tackling this unmet medical needwith personalized therapies [24]. Similarly, the dismalprognosis of glioblastoma largely reflects the fact thatthe standard of care does not target the key oncogenicdrivers, and for most patients is not personalized [25].Diseases with a heterogeneous clinical course, such asprostate cancer, have an equally heterogeneous biol-ogy, which may provide a more informative taxonomyto guide appropriate management with targeted ther-apies [26]. Such classifications must incorporate bothsomatic data and germline polymorphisms if they areto capture the full spectrum of the host–disease inter-action [27]. Molecular classification is fast becominga prerequisite for patients to gain access to the mostnovel approved therapies and to clinical trials of inves-tigational targeted agents; if pathologists do not act toprovide this information in a timely manner, empow-ered patients will usurp the local laboratory and seekit out themselves.
The last decade has seen the translation of biomarkerresearch to companion diagnostic development thatis critical to a drug’s approval. However, the FDA’scurrent model of one companion diagnostic, for onedrug, for one disease is outdated [28]. Prominent aca-demic centres and innovative biotechnology compa-nies [29–31] are developing and investigating robustand reliable multiplex diagnostics to guide treatmentdecisions in the research setting. These advances havenot gone unnoticed by increasingly engaged patients,empowered by the accessibility of their own tis-sue and the falling price of comprehensive next-generation sequencing [30]. In meeting this need, aca-demic pathologists are taking the lead in establishingcutting-edge central laboratories to meet the growingdemands of patients and oncologists.
Despite recent successes of drugs targeting drivermutations in cancer, cures are rare and patients even-tually progress. Single-agent immunotherapies are ableto drive sustained responses in a proportion of can-cer patients, but many more do not respond or showearly resistance [7]. Preliminary data for combinationtherapy in melanoma, with both BRAF /MEK inhibi-tion [32] and PD1 /CTLA4 [21] inhibition, suggestincreased response rates and/or progression-free sur-vival. Therefore, following the model of anti-HIV ther-apy, understanding mechanisms of resistance [33] maylead to personalized combination therapy to improveoutcomes in oncology. Sequencing outstanding respon-ders and unusually resistant patients [34] is an impor-tant first step in this regard. However, we also needto better understand intra- and interpatient heterogene-ity [35,36] of the tumour and its immune response[22], both at baseline and at progression. The provi-sion of tissue at baseline is now mandatory for entryinto many clinical trials, to enable the evaluation offuture companion diagnostics and exploratory biomark-ers. Nevertheless, when the disease progresses and thepatient is in greater need, a repeat biopsy is rarelycollected. In many instances second- and third-line
Copyright 2013 Pathological Society of Great Britain and Ireland. J Pathol 2014; 232: 99–102Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk www.thejournalofpathology.com
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Table 1. The futures of drug development
Now Future
Diseases defined and classified bytheir histology
Diseases defined and classified bytheir molecular pathology
Drugs developed as single agentsor in combination withnon-targeted therapies
Drugs developed in combinationwith other biological or smallmolecule therapies
Single companion diagnosticsdeveloped for individual drugs
Multiplex diagnostics for diseaseentities
Resistance mechanismsinvestigated and understood inretrospect after approval
An understanding of resistance isa key part of preclinicaldevelopment, with trials underway to overcome resistancebefore approval
Progression not defined untilclinical, radiological and/orhistological evidence
Real time monitoring for drugresistance with molecular andchemical pathology, allowingearlier and possibly moreeffective intervention
Archival tissue or baseline biopsiesnot yet mandatory in all clinicaltrials
Biopsies and blood sampling atbaseline, on treatment and atprogression will become anintegral part of clinical trials
trials are conducted using baseline tissue to definebiomarker status. This ignores the spatial and tempo-ral heterogeneity of metastatic and locally advanceddisease [35,36]. It also significantly reduces the likeli-hood of identifying those patients most likely to benefitfrom the drug in question. Partnering with patients,interventional radiologists and institutional reviewboards/ethics committees, pathologists must help toensure that biopsies are taken at progression. Data fromthese biopsies can inform preclinical models of drugresistance, which in turn can identify intelligent drugcombinations and the monitoring of resistance in realtime, using imaging [37] or blood [38]. Returning tothe patient, this approach has the potential to improveoutcomes in second- and third-line disease, but only ifthere is tissue, and only if there is good pathology.
The pace of drug discovery and development hasbeen exponential, but to continue on this trajectoryseveral hurdles must be overcome: (a) we need bettermodels of disease to increase the likelihood that a suc-cessful preclinical drug will translate into a successfulclinical drug [1,2]; (b) pathologists need a multidisci-plinary education to facilitate the development of drugswith novel mechanisms of action [17,22]; (c) relevantmolecular subclassification needs to be rapidly inte-grated into routine practice [23–25]; (d) the regulatoryand technical challenges facing multiplex diagnosticsmust be tackled to enable them to be used for treatmentdecisions [3]; and (e) pathologists need to partner withcolleagues and patients to obtain tissue biopsies of pro-gressive disease that can inform biology and treatmentof resistance [33].
References1. Bates J, Diehl L. Dendritic cells in IBD pathogenesis: an area of
therapeutic opportunity? J Pathol 2014; 232: 112–120.
2. Das Thakur M, Pryer NK, Singh M. Advances in mouse tumourmodels to guide drug development and identify resistance mecha-nisms. J Pathol 2014; 232: 103–111.
3. Shames DS, Wistuba II. The evolving genomic classification of lungcancer. J Pathol 2014; 232: 121–133.
4. Soda M, Takada S, Takeuchi K, et al. A mouse model forEML4–ALK-positive lung cancer. Proc Natl Acad Sci USA 2008;105: 19893–19897.
5. Koeppen H, Rost S, Yauch RL. Developing biomarkers to predictbenefit from HGF–MET pathway inhibitors. J Pathol 2014; 232:210–218.
6. Smith NR, Womack C. A matrix approach to guide IHC-basedtissue biomarker development in oncology drug discovery. J Pathol
2014; 232: 190–198.7. Homet B, Ribas A. New drug targets in metastatic melanoma.
J Pathol 2014; 232: 134–141.8. Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-
type RAF to activate the MAPK pathway and enhance growth.Nature 2010; 464: 431–435.
9. Nagtegaal ID, West NP, van Krieken JHJM, et al. Pathology is anecessary and informative tool in oncology clinical trials. J Pathol
2014; 232: 185–189.10. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor
needs broad target blockade in BRAF -mutant melanoma. Nature
2010; 467: 596–599.11. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study
comparing cisplatin plus gemcitabine with cisplatin plus pemetrexedin chemotherapy-naive patients with advanced-stage non-small-celllung cancer. J Clin Oncol 2008; 26: 3543–3551.
12. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomizedphase II trial comparing bevacizumab plus carboplatin and pacli-taxel with carboplatin and paclitaxel alone in previously untreatedlocally advanced or metastatic non-small-cell lung cancer. J Clin
Oncol 2004; 22: 2184–2191.13. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of
neoadjuvant pertuzumab and trastuzumab in women with locallyadvanced, inflammatory, or early HER2-positive breast cancer(NeoSphere): a randomised multicentre, open-label, phase 2 trial.Lancet Oncol 2012; 13: 25–32.
14. Prowell TM, Pazdur R. Pathological complete response and accel-erated drug approval in early breast cancer. N Engl J Med 2012;366: 2438–2441.
15. Groenen PJ, Blokx WA, Diepenbroek C, et al. Preparing pathologyfor personalized medicine: possibilities for improvement of the pre-analytical phase. Histopathology 2011; 59: 1–7.
16. Simeon-Dubach D, Burt AD, Hall PA. Quality really matters: theneed to improve specimen quality in biomedical research. J Pathol
2012; 228: 431–433.17. van Lookeren Campagne M, LeCouter J, Yaspan BL, et al.
Mechanisms of age-related macular degeneration and therapeuticopportunities. J Pathol 2014; 232: 151–164.
18. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013; 39: 1–10.
19. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, andimmune correlates of anti-PD-1 antibody in cancer. N Engl J Med
2012; 366: 2443–2454.20. Hamid O, Robert C, Daud A, et al. Safety and tumor responses
with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013;369: 134–144.
21. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plusipilimumab in advanced melanoma. N Engl J Med 2013; 369:122–133.
22. Galon J, Mlecnik B, Bindea G, et al. Towards the introduction of theImmunoscore in the classification of malignant tumours. J Pathol
2014; 232: 199–209.
Copyright 2013 Pathological Society of Great Britain and Ireland. J Pathol 2014; 232: 99–102Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk www.thejournalofpathology.com
102 AM Jubb et al
23. Montemurro F, Scaltriti M. Biomarkers of drugs targeting HER-family signalling in cancer. J Pathol 2014; 232: 219–229.
24. Lehmann BD, Pietenpol JA. Identification and use of biomarkersin treatment strategies for triple-negative breast cancer subtypes.J Pathol 2014; 232: 142–150.
25. Olar A, Aldape KD. Using the molecular classification of glioblas-toma to inform personalized treatment. J Pathol 2014; 232:165–177.
26. Rodrigues DN, Butler LM, Llorente D, et al. Molecular pathologyand prostate cancer therapeutics: from biology to bedside. J Pathol2014; 232: 178–184.
27. Smith SA, French T, Hollingsworth SJ. The impact of germlinemutations on targeted therapy. J Pathol 2014; 232: 230–243.
28. Schilsky RL, Doroshow JH, Leblanc M, et al. Development anduse of integral assays in clinical trials. Clin Cancer Res 2012; 18:1540–1546.
29. Sequist LV, Heist RS, Shaw AT, et al. Implementing multiplexedgenotyping of non-small-cell lung cancers into routine clinicalpractice. Ann Oncol 2011; 22: 2616–2624.
30. Eisenstein M. Foundation medicine. Nat Biotechnol 2012; 30: 14.31. Wagle N, Berger MF, Davis MJ, et al. High-throughput detection
of actionable genomic alterations in clinical tumor samples by
targeted, massively parallel sequencing. Cancer Discov 2012; 2:82–93.
32. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK
inhibition in melanoma with BRAF V600 mutations. N Engl J Med2012; 367: 1694–1703.
33. Blair BG, Bardelli A, Park BH. Somatic alterations as the basis forresistance to targeted therapies. J Pathol 2014; 232: 244–254.
34. Weigelt B, Reis-Filho JS. Epistatic interactions and drug response.J Pathol 2014; 232: 255–263.
35. Arnedos M, Viehl P, Soria JC, et al. The genetic complexity ofcommon cancers and the promise of personalized medicine: is thereany hope? J Pathol 2014; 232: 274–282.
36. Crockford A, Jamal-Hanjani M, Hicks J, et al. Implications ofintratumour heterogeneity for treatment stratification. J Pathol
2014; 232: 264–273.37. Vakoc BJ, Fukumura D, Jain RK, et al. Cancer imaging by optical
coherence tomography: preclinical progress and clinical potential.Nat Rev Cancer 2012; 12: 363–368.
38. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutationsand acquired resistance to anti-EGFR therapy in colorectal cancer.Nature 2012; 486: 532–536.
Copyright 2013 Pathological Society of Great Britain and Ireland. J Pathol 2014; 232: 99–102Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk www.thejournalofpathology.com
