- Email: [email protected]
At a crossroads in oncology
Available online at www.sciencedirect.com
At a crossroads in oncology Alexander Kamb We survey the current paradigm for cancer therapy and offer a perspective on the state of clinical oncology. Next, we address the key clinical and biological obstacles that have hampered progress to date. Recent insights into the true genetic complexity of cancer, the mixed clinical performance of targeted therapies, and the homogeneity of industry pipelines argue for new approaches to cancer therapy.
In totality, the preclinical and clinical situations imply that a new approach is warranted. As the nearly 800 cancer drugs in clinical development play out, we should revisit the obstacles that continue to impede progress against cancer, a disease that still claims one in three lives in developed countries.
The current paradigm for cancer therapy Address Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA Corresponding author: Kamb, Alexander ([email protected])
Current Opinion in Pharmacology 2010, 10:356–361 This review comes from a themed issue on Cancer Edited by Raymond Winquist and Diane Boucher Available online 9th June 2010 1471-4892/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2010.05.006
Introduction We find ourselves at a crossroads in oncology research. New technologies produce a flood of genomic data from research labs around the world on a scale far greater than output during the so-called genomics era of the 1990s, a period that seeded many of the oncology drugs registered in the past decade. Meanwhile, we harvest clinical results from numerous Ph 3 studies of the latest crop of targeted therapeutics. With these preclinical and clinical observations, we now discern the horizon of the oncology landscape. An informal survey of oncology pipelines suggests that all large companies, and most small ones, are concentrated on a limited number of mechanisms and targets, for instance, over a dozen molecules in the clinic target IGF-IR or its ligand (source: citeline.com). We may attribute this congestion to several factors: firstly, the lack of compelling new biology that inspires novel target ideas; secondly, the dearth of revolutionary technologies that might enable new approaches; thirdly, the failure to extract interesting targets in sufficient numbers from the vast and complex array of genomics information; and fourthly, the persuasive, homogenizing power of a few therapeutic concepts, including signaling inhibitors and oncogene addiction, among academic and industrial scientists and clinicians. Current Opinion in Pharmacology 2010, 10:356–361
The hallmarks of cancer, those biological processes that characterize all tumors, form the foundation of modern therapeutic approaches [1]. Of 55 cancer therapeutics approved in the past decade, over half are targeted to specific proteins (Table 1). Nearly three quarters of the 55 are based on functional antagonism of cancer cell survival and growth mechanisms. Dysregulated proliferation is the signal feature of cancer and oncology drug discovery has focused intently on the different phases of growth control. Knowledge of the basic biology of cell division, facilitated greatly by evolutionary conservation of many of the fundamental aspects of the cell cycle, has enabled discovery and prosecution of a large number of antiproliferative therapeutics. Such drugs range from traditional cytotoxics to inhibitors of specific protein targets that function at precise points in mitosis (neocytotoxics). Many of the genes that encode these antiproliferative targets are highlighted by somatic mutations that provide direct evidence for their role in the genesis of cancer. Invasion and migration are closely related characteristics of tumor cells, responsible for metastasis and tumor spread. Industry has concentrated on a few antimetastatic targets including metalloproteases and signal-transduction inhibitors (e.g. c-met) [2,3]. To date none has been approved. The fact that antimetastatic agents may be most effective in early stages of cancer — a setting in which new therapeutics are rarely tested — may be one barrier to their successful development. Apoptosis is one of the key systems that ensure cells grow only in their native setting. Normal cells that alight in an abnormal environment often activate suicide programs. This error-correction feature guarantees proper tissue development and protects against autoimmunity and cancer. Tumor cells acquire the capacity to ignore such stimuli, ultimately becoming resistant to a broad set of stressors, including drug therapy. Several experimental therapeutics, such as TRAIL and inhibitors of bcl2, mdm2, and IAP, target these apoptosis pathways, with the aim of selectively activating cell death in tumor cells [4]. www.sciencedirect.com
At a crossroads in oncology Kamb 357
Table 1 Summary of oncology therapeutics FDA approvals, 2000–2009. LM, large molecule therapeutic; SM, small-molecule therapeutic; MoA, mechanism of action (from http://www.centerwatch.com/ drug-information/fda-approvals/drug-areas.aspx?AreaID=12) Drug class
Number (2000–2009)
LM
Novel MoA
Supportive care Traditional cytotoxic Targeted SM Ab or Armed Ab Vaccine
12 11 22 8 2
3 0 0 8 2
5 1 7 1 1
Total
55
13
15
Immortality is a universal feature of malignant cells. Only stem cells possess this trait; other normal cells divide a finite number of times, differentiate or senesce and die. Besides telomerase, the enzyme that lengthens telomeres, few targets have been uncovered with specific roles in cellular lifespan and so far no drugs have entered the clinic which target this mechanism [5]. Angiogenesis is the sole newly appreciated cancer hallmark exploited for clinical benefit in the last decade [6]. Tumors need nutrients carried by blood to grow. Predicted broad activity and add-on potential to other drugs recommend this therapeutic approach for medical and commercial reasons.
Recent clinical oncology results: the major causes of poor efficacy By most measures, clinical trials over the past few years have not expanded upon the initial breakthroughs in targeted cancer therapies represented by Gleevec (app. 2001) on the small-molecule front, and Rituxan (app. 1997) and Herceptin (app. 1998) on the protein therapeutic front. Despite a number of drug approvals, we have seen only modest effects on long-term survival [7]. Pre-existing and acquired resistance in the populations under study, typically the grievously ill, continue Table 2A The ascendant approach: signaling inhibitors in oncology Pros Druggable targets Somatic mutation ‘smoking guns’ Possibility for patient selection in specific cases Some precedent for success (Gleevec and Herceptin) In certain cases, favorable toxicity profiles compared to cytotoxics Cons Complex, interconnected pathways Fluid signaling responses Toxicity versus efficacy trade-offs Mainly modest long-term survival benefits to date Intense competition on most compelling targets Patient selection challenging in general case
www.sciencedirect.com
to render clinical responses infrequent and ephemeral (Table 2A). Cancer drugs fail in the clinic mainly because of lack of efficacy. Three key factors contribute to these failures: firstly, low response rates; secondly, relapse; and thirdly, dose-limiting on-mechanism toxicities. The poor outcomes often observed in early clinical trials of novel therapeutics have a variety of causes, the most important of which may be the rugged constitution of tumor cells in the advanced setting. Most of the patients enrolled in such studies have failed multiple therapies and have developed resistance mechanisms that extend beyond the specific treatments of their prior regimens [7]. A distinct but related reason for low response rates involves the complexity and heterogeneity of cancer. At the epigenetic and phenotypic levels, cancer is a myriad of different diseases with hundreds of subtypes described by pathologists [8]. A subset of these histological types responds well to specific drugs, but not to others. For instance, Gleevec is effective in chronic myelogenous leukemia (CML), but not in other leukemias [9]. Somatic mutations that individual tumors acquire add to the complexity. In the future, scientists and clinicians may define the criteria for drug response, allowing therapies to be personalized to individual tumors based on their epigenetic and genomic profiles. However, this approach has proved difficult to generalize beyond some special, and in retrospect obvious, cases. For example, the Her2/Neu antibody, Herceptin, works much better in breast tumors that contain amplified Her2/Neu genes, and the EGFR antibody, Vectibix, is ineffective in colorectal cancer patients whose tumors bear a mutant K-ras gene that short-circuits the receptor [10,11]. Moreover, when a responder population can be delimited, the patient numbers are often small, raising questions about the financial return for companies that invest in the development of such patient-selective, niche drugs. Even in cases where patients enjoy dramatic tumor regressions, the responses are all too often short-lived. Acquired drug resistance and residual disease are the culprits behind such relapses. One traditional means of combating relapse, pioneered in the infectious disease setting, involves drug combinations. Indeed, combinations of therapeutics have been the standard for cancer therapy for nearly 40 years, and are largely responsible for the cures that modern medicine can bring [12]. The success of combination therapy is due in part to the elimination of cancer cell subclones that harbor resistance mutations. The downside of such approaches, apart from the difficulties of choosing and testing the best combination Current Opinion in Pharmacology 2010, 10:356–361
358 Cancer
partners, is the potential for increased toxicity as more cellular mechanisms fall under simultaneous attack [13].
to defy such impulses, while avoiding normal cells which have the opposite evolutionary trajectory, is considerable.
One variation worth considering involves the creation of therapeutics that combine two antagonist/agonist activities in one — dual-targeted drugs. For biologics, given the modular structure of proteins, the design of bifunctional therapeutics is relatively straightforward. For smallmolecule drugs, the identification and optimization of molecules that hit two targets simultaneously, and avoid the large majority of other drug targets, is especially challenging. An exception is targets with substantial structural similarity, as in the case of Tykerb, which inhibits both EGFR and its close homolog Her2/Neu [14]. The drive to optimize toward potency and specificity may fall short of the goal, leaving the drug developers with a multi-targeted agent, sometimes adorned with the name spectrum-selective inhibitor [15]. Whether or not these drugs are generally better than highly specific antagonists due to broader efficacy, or worse, due to doselimiting toxicities, remains to be seen. For both approaches — proteins and small molecules — the trade-off is between cost of goods and relatively clear development path on the one hand, and technical feasibility and dosing flexibility on the other.
Exceptions prove the rule. The Abl gene is not required in adult tissues, but is the key driver of CML cells [9]. But Gleevec is so far unique — no oncology drug since its approval nearly 10 years ago has performed nearly so well. Instead, most cancer drugs modulate functions that are shared between tumor and normal cells. These range from general antiproliferative, cytotoxic drugs, to focal cytotoxics that target functions common to certain tissues and tumors derived from those tissues (e.g., estrogen receptor). The multifactorial and networked aspects of cell growth function, and the therapeutic window — the reliance of normal cell growth on the same set of mechanisms — hamper the success of this class of agents.
We may fantasize about more potent therapeutic mechanisms, capable of generating more substantial, and perhaps more wide-ranging responses. Experience and first principles suggest, however, that such approaches carry the risk of increased toxicity. The low-toxicity targets for small-molecule magic bullets and recurrent tumorspecific antigens appear to be very rare (Figure 1). Tumors draw on the same gene functions as normal cells. Therefore, tumors likely have dependencies similar to their normal counterparts. Oncogene and tumor suppressor gene alteration may improve, not diminish, a cell’s fitness. For instance, it is hard to see how inactivation of apoptotic mechanisms impairs cancer cells. Rather, apoptotic machinery is an impediment that, once removed, confers selective advantage, not weakness. The challenge of triggering apoptosis in a cancer cell, which has evolved
Figure 1
Categories of anticancer drugs and predicted on-mechanism toxicity, with requirement of protein function below. In general, anticancer activity and normal cell toxicity are expected to be inversely related. Current Opinion in Pharmacology 2010, 10:356–361
If the normal cells tolerate a specific stress, it is likely that tumor cells will also endure it, except in unusual circumstances. The record of antiangiogenic agents such as Genentech’s Avastin bears out this view. Avastin is well tolerated by comparison with many cytotoxic drugs. But despite the biological validation of the approach, so far the improvements in long-term survival, even in first-line therapy, have been disappointing [16,17]. A possible explanation for the limited efficacy is the role of micrometastases in poor survival. Plenty of blood vessels exist to service normal tissues and these can be co-opted by a resourceful tumor. A mechanism that is nonessential in adult normal tissues, is likely to be dispensable in tumors as well.
Recent oncology research results: the new view of somatic variation In cancer research, the most important body of work of the past few years comprises genomic sequences of primary tumor samples, metastases and cell lines [18,19,20,21]. These data demonstrate that tumorigenesis in situ is drastically more complex than the models that have held sway over the past two decades (e.g. Vogelgram, two-hit hypothesis). The latest ultrahigh-throughput sequencing data reveal a shocking degree of variation between tumors and parental genomes: dozens of chromosome rearrangements, hundreds of microdeletion/insertions, and tens of thousands of nucleotide substitutions. Dozens to hundreds of these genetic changes alter protein sequences, with minimal overlap among different primary tumors. This pattern and load of mutations are consistent with the idea that cancer phenotypes are more akin to polygenic, quantitative traits than simple Mendelian ones, and imply that biologists will need to sort through a myriad of weak effects and random changes in order to find the important ones. Although a comprehensive catalog of somatic changes is in its early stages, the results to date imply that firstly, the recurrence rates of the vast majority of somatic variants www.sciencedirect.com
At a crossroads in oncology Kamb 359
are low; secondly, the more common ones are already known; and thirdly, the majority of somatic variants have little effect on tumor evolution (i.e. are not under genetic selection). In addition to the revelation of extreme genetic complexity, recent sequencing data indicate that the vast majority of somatic mutations occur before metastasis, at least in colon cancer [18]. The metastatic process itself involves few, if any, additional changes. Thus, we may question attempts to target metastases as distinct genetic entities. Another important outcome of these large-scale sequencing efforts is compelling evidence that adaptation per se of primary tumor cells to tissue culture introduces few additional mutations [18]. Thus, paradoxically, DNA sequencing tells us that though cancer is far more complex and heterogeneous than expected, the slew of genetic changes that occur during formation of the primary tumor are largely sufficient to generate metastases and tissue culture lines. This conclusion undermines the notion that the poor record of prediction for oncology preclinical models can be attributed to the genetic mismatch between tissue-culture-adapted cell lines and real tumors, including metastatic lesions [22].
An alternative: harnessing the immune system Although few true tumor-specific antigens exist — at least in the sense once hoped for — recent studies of tumor genomes demonstrate the potential for a tremendous amount of antigenic variation, the vast majority of which is private to each tumor. It is tempting to speculate that such variation will ultimately prove to be their undoing. But so far, cancer immunotherapy has remained a promising, yet unfulfilled, therapeutic possibility (Table 2B). Three general immunotherapy approaches have dominated the clinical scene: active immunization, passive immunization, and immunomodulation. Active immunization is akin to vaccination with tumor antigens, DNA or tumor cell preparations. The idea is to generate an immune response directed specifically against tumor antigens that the immune system recognizes as foreign [23]. This approach has been pursued for several decades, so far with marginal success, though the likely registration of Sipuleucel-T (Provenge) in prostate cancer is encouraging [24]. Potential explanations for the modest efficacy include: firstly, tolerance to tumor antigens; secondly, logistical difficulties related to antigen preparation; and thirdly, immunosuppression in cancer patients. Passive immunization seeks to sidestep the need to activate an immune response by the delivery of antiwww.sciencedirect.com
Table 2B An alternative approach: immunotherapy in oncology Pros Deliberate, externally applied death blow Promise of harnessing ingenuity of immune system for specific antitumor response Cons Recurrent, surface accessible, truly tumor-specific antigens very rare Immune tolerance to tumors evident Safety questions when tolerance broken Problematic preclinical models Black-box nature of effector component in vivo
bodies or other proteins directed against tumor antigens [25]. The passive approach can be further divided into categories that employ either armed molecules that deliver warheads to the tumor cells, or naked antibodies that utilize the effector mechanisms that operate in a native immune response, including antibody-dependent cellular cytotoxicity (CD20, Rituxan) and complement-dependent cytotoxicity (CD20, Arzerra), or exert direct antagonistic effects on growth by the inhibition of signaling pathways (e.g. Herceptin). Despite several spectacular successes, the approach has not evolved into a widely employed anticancer treatment option. Possible reasons include: firstly, poor preclinical models for efficacy and toxicity based on non-rodent-reactive antibodies; secondly, problematic relationships between rodent immune effector mechanisms and human ones (e.g. FcRs and antibody Fcs) [26]; thirdly, production challenges of armed antibodies; and fourthly, lack of recurrent, highquality targets that are present selectively on the tumor surface in large amounts. Immunomodulation strives to amplify an antitumor immune response that is presumed to be ongoing, but insufficient to control the cancer. The paradigm for this approach is the naked antibody drug, Ipilimumab, that blocks the T-cell inhibitory protein CTLA-4 expressed on the surface of antigen-presenting cells [27]. This drug, now in Ph 3, has shown promise in melanoma and prostate cancer clinical trials. The principal weaknesses of this strategy are: firstly, the risk of activating generalized autoimmunity and secondly, the dependence for efficacy and therapeutic window on a dormant antitumor response.
Conclusion It is increasingly evident that the promise of molecularly targeted therapies remains elusive. Some of the traditional improvements, combination therapy, for instance, may produce results closer to initial expectations. Another possibility is that detailed molecular analysis of tumors, coupled with improved understanding of gene functions, may provide the boost needed for a larger number of personalized therapies. Immunologic Current Opinion in Pharmacology 2010, 10:356–361
360 Cancer
approaches also continue to inspire hope. But the clinical evidence to date suggests that new ideas, or at least meaningful twists on these current ideas, are required to realize more of the potential that has captivated oncology researchers and clinicians for the past two decades.
12. Frei E, Eder JP: Principles of dose, schedule, and combination. Cancer Medicine. BC Decker, Inc; 2003.
Acknowledgement
14. Tevaarwerk AJ, Kolesar JM: Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer. Clin Ther 2009, 31:2332-2348. A good review of a dual-targeted drug that may provide distinct advantages over the mono-targeted therapeutics.
The author thanks Drs David Reese and Dineli Wickramasinghe for comments on the manuscript.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.coph. 2010.05.006.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1. Mantovani A: Cancer: inflaming metastasis. Nature 2009, 457:36-37. A good updated overview of the hallmarks of cancer, originally described by Hanahan and Weinberg. 2.
Roy R, Yang J, Moses MA: Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J Clin Oncol 2009, 27:5287-5297.
3.
Underiner TL, Herbertz T, Miknyoczki SJ: Discovery of small molecule c-met inhibitors: evolution and profiles of clinical candidates. Anticancer Agents Med Chem 2009, 10:7-27.
4.
Fesik SW: Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 2005, 5:876-885.
5.
Harley CB: Telomerase and cancer therapeutics. Nat Rev Cancer 2008, 8:167-179.
6.
Crawford Y, Ferrara N: VEGF inhibition: insights from preclinical and clinical studies. Cell Tissue Res 2009, 335:261-269.
7. Stewart DJ, Kurzrock R: Cancer: the road to Amiens. J Clin Oncol 2009, 27:328-333. A provocative and probing look at the underwhelming performance of investigational cancer drugs in the clinic over the past few years. The authors make some recommendations on how to improve the situation. 8.
Fritz A, Percy C, Jack A (Eds): et al.: ICD-O-3: International Classification of Disease for Oncology, edn 3. Geneva: World Health Organization; 2000, http://seer.cancer.gov/icd-o-3/ sitetype.icdo3.d20091204.pdf.
9.
Quinta´s-Cardama A, Kantarjian H, Cortes J: Imatinib and beyond — exploring the full potential of targeted therapy for CML. Nat Rev Clin Oncol 2009, 6:535-543.
10. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002, 20:719-726. 11. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008, 26:1626-1634. An instructive example of patient selection in oncology — in this case for nonresponse to an EGFR antagonist. This work illustrates how a rather obvious patient selection criterion (K-ras activation) can take years to establish clinically. Current Opinion in Pharmacology 2010, 10:356–361
13. Horton TM, Sposto R, Brown P, Reynolds CP, Hunger SP, Winick NJ, Raetz EA, Carroll WL, Arceci RJ, Borowitz MJ et al.: Toxicity assessment of molecularly targeted drugs incorporated into multiagent chemotherapy regimens for pediatric acute lymphocytic leukemia (ALL): Review from an international consensus conference. Pediatr Blood Cancer 2010, 54:872-878.
15. Klebl BM, Mueller G: Second-generation kinase inhibitors. Expert Opin Ther Targets 2005, 9:975-993. 16. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd, Eastern Cooperative Oncology Group Study E3200: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007, 25:1539-1544. 17. Okines A, Cunningham D: Current perspective: bevacizumab in colorectal cancer–a time for reappraisal? Eur J Cancer 2009, 45:2452-2461. A paper that takes a critical look at the value of Avastin in light of its lack of long-term benefit to patients, at least so far. 18. Jones S, Chen WD, Parmigiani G, Diehl F, Beerenwinkel N, Antal T, Traulsen A, Nowak MA, Siegel C, Velculescu VE et al.: Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci U S A 2008, 105:4283-4288. A very interesting paper that uses large-scale Sanger sequencing to approach several important questions in the natural history of tumors. The authors find that only a tiny percentage of new mutations occurs in colon metastases and cell lines, compared to the primary tumors from which they were derived. 19. Pleasance ED, Stephens PJ, O’Meara S, McBride DJ, Meynert A, Jones D, Lin ML, Beare D, Lau KW, Greenman C et al.: A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 2010, 463:184-190. A comprehensive look through ultra-high-throughput sequencing at a lung cancer genome compared with the DNA from the genome of a normal cell from the patient. The results show 23 000 base substitutions, 94 of which cause amino acid substitutions in predicted proteins — approximately what is expected by chance (i.e. no evidence for evolutionary selection), as well as 300 deletions/insertions and 60 rearrangements. 20. Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, Varela I, Lin ML, Ordo´n˜ez GR, Bignell GR et al.: A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 2010, 463:191-196. A detailed examination through DNA sequencing of somatic variation in a melanoma tumor line, compared to the patient’s normal genome. Results are: 33 000 nucleotide/dinucleotide changes, 200 nonsynonymous with no evidence for selection; 1000 small deletions/insertions and 50 rearrangements. 21. Stephens PJ, McBride DJ, Lin ML, Varela I, Pleasance ED, Simpson JT, Stebbings LA, Leroy C, Edkins S, Mudie LJ et al.: Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 2009, 462:1005-1010. A close look at genomic rearrangements in breast cancer cell lines and primary breast tumors. Of the 29 in-frame protein fusions identified among 24 cell lines, none is detected in an additional sample of 288 primary breast cancers. 22. Kamb A: What’s wrong with our cancer models? Nat Rev Drug Discov 2005, 4:161-165. 23. Wang E, Monaco A, Monsurro´ V, Sabatino M, Pos Z, Uccellini L, Wang J, Worschech A, Stroncek DF, Marincola FM: Antitumor vaccines, immunotherapy and the immunological constant of rejection. IDrugs 2009, 12:297-301. www.sciencedirect.com
At a crossroads in oncology Kamb 361
24. Drake CG: Immunotherapy for prostate cancer: walk, don’t run. J Clin Oncol 2009, 27:4035-4037.
An excellent review by a master in the increasingly important field of antibody effector functions.
25. Weiner GJ: Monoclonal antibody mechanisms of action in cancer. Immunol Res 2007, 39:271-278.
27. Movva S, Verschraegen C: The monoclonal antibody to cytotoxic T lymphocyte antigen 4, ipilimumab (MDX-010), a novel treatment strategy in cancer management. Expert Opin Biol Ther 2009, 9:231-241.
26. Ravetch J: In vivo veritas: the surprising roles of Fc receptors in immunity. Nat Immunol 2010, 11:183-185.
www.sciencedirect.com
Current Opinion in Pharmacology 2010, 10:356–361
At a crossroads in oncology Alexander Kamb We survey the current paradigm for cancer therapy and offer a perspective on the state of clinical oncology. Next, we address the key clinical and biological obstacles that have hampered progress to date. Recent insights into the true genetic complexity of cancer, the mixed clinical performance of targeted therapies, and the homogeneity of industry pipelines argue for new approaches to cancer therapy.
In totality, the preclinical and clinical situations imply that a new approach is warranted. As the nearly 800 cancer drugs in clinical development play out, we should revisit the obstacles that continue to impede progress against cancer, a disease that still claims one in three lives in developed countries.
The current paradigm for cancer therapy Address Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA Corresponding author: Kamb, Alexander ([email protected])
Current Opinion in Pharmacology 2010, 10:356–361 This review comes from a themed issue on Cancer Edited by Raymond Winquist and Diane Boucher Available online 9th June 2010 1471-4892/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2010.05.006
Introduction We find ourselves at a crossroads in oncology research. New technologies produce a flood of genomic data from research labs around the world on a scale far greater than output during the so-called genomics era of the 1990s, a period that seeded many of the oncology drugs registered in the past decade. Meanwhile, we harvest clinical results from numerous Ph 3 studies of the latest crop of targeted therapeutics. With these preclinical and clinical observations, we now discern the horizon of the oncology landscape. An informal survey of oncology pipelines suggests that all large companies, and most small ones, are concentrated on a limited number of mechanisms and targets, for instance, over a dozen molecules in the clinic target IGF-IR or its ligand (source: citeline.com). We may attribute this congestion to several factors: firstly, the lack of compelling new biology that inspires novel target ideas; secondly, the dearth of revolutionary technologies that might enable new approaches; thirdly, the failure to extract interesting targets in sufficient numbers from the vast and complex array of genomics information; and fourthly, the persuasive, homogenizing power of a few therapeutic concepts, including signaling inhibitors and oncogene addiction, among academic and industrial scientists and clinicians. Current Opinion in Pharmacology 2010, 10:356–361
The hallmarks of cancer, those biological processes that characterize all tumors, form the foundation of modern therapeutic approaches [1]. Of 55 cancer therapeutics approved in the past decade, over half are targeted to specific proteins (Table 1). Nearly three quarters of the 55 are based on functional antagonism of cancer cell survival and growth mechanisms. Dysregulated proliferation is the signal feature of cancer and oncology drug discovery has focused intently on the different phases of growth control. Knowledge of the basic biology of cell division, facilitated greatly by evolutionary conservation of many of the fundamental aspects of the cell cycle, has enabled discovery and prosecution of a large number of antiproliferative therapeutics. Such drugs range from traditional cytotoxics to inhibitors of specific protein targets that function at precise points in mitosis (neocytotoxics). Many of the genes that encode these antiproliferative targets are highlighted by somatic mutations that provide direct evidence for their role in the genesis of cancer. Invasion and migration are closely related characteristics of tumor cells, responsible for metastasis and tumor spread. Industry has concentrated on a few antimetastatic targets including metalloproteases and signal-transduction inhibitors (e.g. c-met) [2,3]. To date none has been approved. The fact that antimetastatic agents may be most effective in early stages of cancer — a setting in which new therapeutics are rarely tested — may be one barrier to their successful development. Apoptosis is one of the key systems that ensure cells grow only in their native setting. Normal cells that alight in an abnormal environment often activate suicide programs. This error-correction feature guarantees proper tissue development and protects against autoimmunity and cancer. Tumor cells acquire the capacity to ignore such stimuli, ultimately becoming resistant to a broad set of stressors, including drug therapy. Several experimental therapeutics, such as TRAIL and inhibitors of bcl2, mdm2, and IAP, target these apoptosis pathways, with the aim of selectively activating cell death in tumor cells [4]. www.sciencedirect.com
At a crossroads in oncology Kamb 357
Table 1 Summary of oncology therapeutics FDA approvals, 2000–2009. LM, large molecule therapeutic; SM, small-molecule therapeutic; MoA, mechanism of action (from http://www.centerwatch.com/ drug-information/fda-approvals/drug-areas.aspx?AreaID=12) Drug class
Number (2000–2009)
LM
Novel MoA
Supportive care Traditional cytotoxic Targeted SM Ab or Armed Ab Vaccine
12 11 22 8 2
3 0 0 8 2
5 1 7 1 1
Total
55
13
15
Immortality is a universal feature of malignant cells. Only stem cells possess this trait; other normal cells divide a finite number of times, differentiate or senesce and die. Besides telomerase, the enzyme that lengthens telomeres, few targets have been uncovered with specific roles in cellular lifespan and so far no drugs have entered the clinic which target this mechanism [5]. Angiogenesis is the sole newly appreciated cancer hallmark exploited for clinical benefit in the last decade [6]. Tumors need nutrients carried by blood to grow. Predicted broad activity and add-on potential to other drugs recommend this therapeutic approach for medical and commercial reasons.
Recent clinical oncology results: the major causes of poor efficacy By most measures, clinical trials over the past few years have not expanded upon the initial breakthroughs in targeted cancer therapies represented by Gleevec (app. 2001) on the small-molecule front, and Rituxan (app. 1997) and Herceptin (app. 1998) on the protein therapeutic front. Despite a number of drug approvals, we have seen only modest effects on long-term survival [7]. Pre-existing and acquired resistance in the populations under study, typically the grievously ill, continue Table 2A The ascendant approach: signaling inhibitors in oncology Pros Druggable targets Somatic mutation ‘smoking guns’ Possibility for patient selection in specific cases Some precedent for success (Gleevec and Herceptin) In certain cases, favorable toxicity profiles compared to cytotoxics Cons Complex, interconnected pathways Fluid signaling responses Toxicity versus efficacy trade-offs Mainly modest long-term survival benefits to date Intense competition on most compelling targets Patient selection challenging in general case
www.sciencedirect.com
to render clinical responses infrequent and ephemeral (Table 2A). Cancer drugs fail in the clinic mainly because of lack of efficacy. Three key factors contribute to these failures: firstly, low response rates; secondly, relapse; and thirdly, dose-limiting on-mechanism toxicities. The poor outcomes often observed in early clinical trials of novel therapeutics have a variety of causes, the most important of which may be the rugged constitution of tumor cells in the advanced setting. Most of the patients enrolled in such studies have failed multiple therapies and have developed resistance mechanisms that extend beyond the specific treatments of their prior regimens [7]. A distinct but related reason for low response rates involves the complexity and heterogeneity of cancer. At the epigenetic and phenotypic levels, cancer is a myriad of different diseases with hundreds of subtypes described by pathologists [8]. A subset of these histological types responds well to specific drugs, but not to others. For instance, Gleevec is effective in chronic myelogenous leukemia (CML), but not in other leukemias [9]. Somatic mutations that individual tumors acquire add to the complexity. In the future, scientists and clinicians may define the criteria for drug response, allowing therapies to be personalized to individual tumors based on their epigenetic and genomic profiles. However, this approach has proved difficult to generalize beyond some special, and in retrospect obvious, cases. For example, the Her2/Neu antibody, Herceptin, works much better in breast tumors that contain amplified Her2/Neu genes, and the EGFR antibody, Vectibix, is ineffective in colorectal cancer patients whose tumors bear a mutant K-ras gene that short-circuits the receptor [10,11]. Moreover, when a responder population can be delimited, the patient numbers are often small, raising questions about the financial return for companies that invest in the development of such patient-selective, niche drugs. Even in cases where patients enjoy dramatic tumor regressions, the responses are all too often short-lived. Acquired drug resistance and residual disease are the culprits behind such relapses. One traditional means of combating relapse, pioneered in the infectious disease setting, involves drug combinations. Indeed, combinations of therapeutics have been the standard for cancer therapy for nearly 40 years, and are largely responsible for the cures that modern medicine can bring [12]. The success of combination therapy is due in part to the elimination of cancer cell subclones that harbor resistance mutations. The downside of such approaches, apart from the difficulties of choosing and testing the best combination Current Opinion in Pharmacology 2010, 10:356–361
358 Cancer
partners, is the potential for increased toxicity as more cellular mechanisms fall under simultaneous attack [13].
to defy such impulses, while avoiding normal cells which have the opposite evolutionary trajectory, is considerable.
One variation worth considering involves the creation of therapeutics that combine two antagonist/agonist activities in one — dual-targeted drugs. For biologics, given the modular structure of proteins, the design of bifunctional therapeutics is relatively straightforward. For smallmolecule drugs, the identification and optimization of molecules that hit two targets simultaneously, and avoid the large majority of other drug targets, is especially challenging. An exception is targets with substantial structural similarity, as in the case of Tykerb, which inhibits both EGFR and its close homolog Her2/Neu [14]. The drive to optimize toward potency and specificity may fall short of the goal, leaving the drug developers with a multi-targeted agent, sometimes adorned with the name spectrum-selective inhibitor [15]. Whether or not these drugs are generally better than highly specific antagonists due to broader efficacy, or worse, due to doselimiting toxicities, remains to be seen. For both approaches — proteins and small molecules — the trade-off is between cost of goods and relatively clear development path on the one hand, and technical feasibility and dosing flexibility on the other.
Exceptions prove the rule. The Abl gene is not required in adult tissues, but is the key driver of CML cells [9]. But Gleevec is so far unique — no oncology drug since its approval nearly 10 years ago has performed nearly so well. Instead, most cancer drugs modulate functions that are shared between tumor and normal cells. These range from general antiproliferative, cytotoxic drugs, to focal cytotoxics that target functions common to certain tissues and tumors derived from those tissues (e.g., estrogen receptor). The multifactorial and networked aspects of cell growth function, and the therapeutic window — the reliance of normal cell growth on the same set of mechanisms — hamper the success of this class of agents.
We may fantasize about more potent therapeutic mechanisms, capable of generating more substantial, and perhaps more wide-ranging responses. Experience and first principles suggest, however, that such approaches carry the risk of increased toxicity. The low-toxicity targets for small-molecule magic bullets and recurrent tumorspecific antigens appear to be very rare (Figure 1). Tumors draw on the same gene functions as normal cells. Therefore, tumors likely have dependencies similar to their normal counterparts. Oncogene and tumor suppressor gene alteration may improve, not diminish, a cell’s fitness. For instance, it is hard to see how inactivation of apoptotic mechanisms impairs cancer cells. Rather, apoptotic machinery is an impediment that, once removed, confers selective advantage, not weakness. The challenge of triggering apoptosis in a cancer cell, which has evolved
Figure 1
Categories of anticancer drugs and predicted on-mechanism toxicity, with requirement of protein function below. In general, anticancer activity and normal cell toxicity are expected to be inversely related. Current Opinion in Pharmacology 2010, 10:356–361
If the normal cells tolerate a specific stress, it is likely that tumor cells will also endure it, except in unusual circumstances. The record of antiangiogenic agents such as Genentech’s Avastin bears out this view. Avastin is well tolerated by comparison with many cytotoxic drugs. But despite the biological validation of the approach, so far the improvements in long-term survival, even in first-line therapy, have been disappointing [16,17]. A possible explanation for the limited efficacy is the role of micrometastases in poor survival. Plenty of blood vessels exist to service normal tissues and these can be co-opted by a resourceful tumor. A mechanism that is nonessential in adult normal tissues, is likely to be dispensable in tumors as well.
Recent oncology research results: the new view of somatic variation In cancer research, the most important body of work of the past few years comprises genomic sequences of primary tumor samples, metastases and cell lines [18,19,20,21]. These data demonstrate that tumorigenesis in situ is drastically more complex than the models that have held sway over the past two decades (e.g. Vogelgram, two-hit hypothesis). The latest ultrahigh-throughput sequencing data reveal a shocking degree of variation between tumors and parental genomes: dozens of chromosome rearrangements, hundreds of microdeletion/insertions, and tens of thousands of nucleotide substitutions. Dozens to hundreds of these genetic changes alter protein sequences, with minimal overlap among different primary tumors. This pattern and load of mutations are consistent with the idea that cancer phenotypes are more akin to polygenic, quantitative traits than simple Mendelian ones, and imply that biologists will need to sort through a myriad of weak effects and random changes in order to find the important ones. Although a comprehensive catalog of somatic changes is in its early stages, the results to date imply that firstly, the recurrence rates of the vast majority of somatic variants www.sciencedirect.com
At a crossroads in oncology Kamb 359
are low; secondly, the more common ones are already known; and thirdly, the majority of somatic variants have little effect on tumor evolution (i.e. are not under genetic selection). In addition to the revelation of extreme genetic complexity, recent sequencing data indicate that the vast majority of somatic mutations occur before metastasis, at least in colon cancer [18]. The metastatic process itself involves few, if any, additional changes. Thus, we may question attempts to target metastases as distinct genetic entities. Another important outcome of these large-scale sequencing efforts is compelling evidence that adaptation per se of primary tumor cells to tissue culture introduces few additional mutations [18]. Thus, paradoxically, DNA sequencing tells us that though cancer is far more complex and heterogeneous than expected, the slew of genetic changes that occur during formation of the primary tumor are largely sufficient to generate metastases and tissue culture lines. This conclusion undermines the notion that the poor record of prediction for oncology preclinical models can be attributed to the genetic mismatch between tissue-culture-adapted cell lines and real tumors, including metastatic lesions [22].
An alternative: harnessing the immune system Although few true tumor-specific antigens exist — at least in the sense once hoped for — recent studies of tumor genomes demonstrate the potential for a tremendous amount of antigenic variation, the vast majority of which is private to each tumor. It is tempting to speculate that such variation will ultimately prove to be their undoing. But so far, cancer immunotherapy has remained a promising, yet unfulfilled, therapeutic possibility (Table 2B). Three general immunotherapy approaches have dominated the clinical scene: active immunization, passive immunization, and immunomodulation. Active immunization is akin to vaccination with tumor antigens, DNA or tumor cell preparations. The idea is to generate an immune response directed specifically against tumor antigens that the immune system recognizes as foreign [23]. This approach has been pursued for several decades, so far with marginal success, though the likely registration of Sipuleucel-T (Provenge) in prostate cancer is encouraging [24]. Potential explanations for the modest efficacy include: firstly, tolerance to tumor antigens; secondly, logistical difficulties related to antigen preparation; and thirdly, immunosuppression in cancer patients. Passive immunization seeks to sidestep the need to activate an immune response by the delivery of antiwww.sciencedirect.com
Table 2B An alternative approach: immunotherapy in oncology Pros Deliberate, externally applied death blow Promise of harnessing ingenuity of immune system for specific antitumor response Cons Recurrent, surface accessible, truly tumor-specific antigens very rare Immune tolerance to tumors evident Safety questions when tolerance broken Problematic preclinical models Black-box nature of effector component in vivo
bodies or other proteins directed against tumor antigens [25]. The passive approach can be further divided into categories that employ either armed molecules that deliver warheads to the tumor cells, or naked antibodies that utilize the effector mechanisms that operate in a native immune response, including antibody-dependent cellular cytotoxicity (CD20, Rituxan) and complement-dependent cytotoxicity (CD20, Arzerra), or exert direct antagonistic effects on growth by the inhibition of signaling pathways (e.g. Herceptin). Despite several spectacular successes, the approach has not evolved into a widely employed anticancer treatment option. Possible reasons include: firstly, poor preclinical models for efficacy and toxicity based on non-rodent-reactive antibodies; secondly, problematic relationships between rodent immune effector mechanisms and human ones (e.g. FcRs and antibody Fcs) [26]; thirdly, production challenges of armed antibodies; and fourthly, lack of recurrent, highquality targets that are present selectively on the tumor surface in large amounts. Immunomodulation strives to amplify an antitumor immune response that is presumed to be ongoing, but insufficient to control the cancer. The paradigm for this approach is the naked antibody drug, Ipilimumab, that blocks the T-cell inhibitory protein CTLA-4 expressed on the surface of antigen-presenting cells [27]. This drug, now in Ph 3, has shown promise in melanoma and prostate cancer clinical trials. The principal weaknesses of this strategy are: firstly, the risk of activating generalized autoimmunity and secondly, the dependence for efficacy and therapeutic window on a dormant antitumor response.
Conclusion It is increasingly evident that the promise of molecularly targeted therapies remains elusive. Some of the traditional improvements, combination therapy, for instance, may produce results closer to initial expectations. Another possibility is that detailed molecular analysis of tumors, coupled with improved understanding of gene functions, may provide the boost needed for a larger number of personalized therapies. Immunologic Current Opinion in Pharmacology 2010, 10:356–361
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approaches also continue to inspire hope. But the clinical evidence to date suggests that new ideas, or at least meaningful twists on these current ideas, are required to realize more of the potential that has captivated oncology researchers and clinicians for the past two decades.
12. Frei E, Eder JP: Principles of dose, schedule, and combination. Cancer Medicine. BC Decker, Inc; 2003.
Acknowledgement
14. Tevaarwerk AJ, Kolesar JM: Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer. Clin Ther 2009, 31:2332-2348. A good review of a dual-targeted drug that may provide distinct advantages over the mono-targeted therapeutics.
The author thanks Drs David Reese and Dineli Wickramasinghe for comments on the manuscript.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.coph. 2010.05.006.
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