Originally published as JCO Early Release 10.1200/JCO.2006.05.9808 on June 12 2006

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Lately, It Occurs to Me What a Long, Strange Trip It's Been for the Farnesyltransferase Inhibitors

ImClone Systems Incorporated, New York, NY

If you had told me 5 years ago that I would be writing a commentary on an exciting report on the prospects of incorporating the farnesyltransferase (FTase) inhibitors, the class of agents that ushered in the era of rationally designed, targeted-based anticancer therapeutics, into the neoadjuvant treatment of breast cancer with doxorubicin and cyclophosphamide (AC),¹ I might have called you crazy, among other expletives. But, to borrow an expression from the contemporary prophets, the Grateful Dead, "what a long strange trip it's been" for the FTase inhibitors! Nevertheless, after considering that long strange trips are actually more common than expected for anticancer therapeutics that are ultimately incorporated into our therapeutic armamentarium, an apology for any untoward remarks would have been forthcoming. Unfortunately, these long strange trips reflect the complexity of the cancer cell and our ignorance in predicting whether subtle changes induced by new therapeutics in the environment of a cancer cell, which is undergoing an inordinate amount of simultaneous biochemical processes in a primordial soup of chemicals and enzymes, will result in a relevant therapeutic response. And, if so, what will be the nature of the response?

Yet, targeting FTase made so much sense to many of us who knew just enough biochemistry, cell biology, and pharmacology to be dangerous (and you know who you are!), and Big Pharma was vested in the prospects that FTase inhibitors had reasonable blockbuster potential based on somewhat teleologic presumptions, which, in hindsight, were incorrect.^2,3 Like other rationally designed, target-based agents, the FTase inhibitors were designed to disrupt fundamental aberrations in malignant cells, whereas normal cells, whose growth and sustenance are not principally dependent on or driven by the target itself or aberrations of the target, were supposed to be spared.^2-5 Preferential tumor growth inhibition, by perturbing the equilibrium between cancer cell proliferation and death, is tantamount to the Holy Grail in oncology therapeutics, and the optimal development of anticancer drugs is all about exploiting therapeutic indices, that is, maximizing activity-toxicity quotients.⁵ Even agents with modest anticancer activity with highly favorable therapeutic indices may be useful in the clinic if the favorable therapeutic indices increase breathing room or the potential to administer them in combination with relevant doses of other agents with much narrower therapeutic indices. A core determinant of the therapeutic index is the redundancy of critical cellular functions in living cells, with these redundant systems evolving over billions of years as a result of selection pressure.^5-8 Because of the high genomic instability of malignant cells, billions of years of selection pressure are, in essence, collapsed into the lifetime of a tumor, which is much more adept at exploiting redundant cellular processes than normal tissues. For this reason, among many others, administering single agents with the intent of imparting a major therapeutic response is usually tantamount to spitting into the ocean. In other words, unless the tumor is driven by a dominant aberration of the target, its redundant cellular processes will eventually overcome the insult.

We often marvel about the complexity of living systems, but, ironically, the complexity of life is all about its simplicity. This paradox is illustrated by considering how innumerable numbers of cellular constituents perform an unfathomable amount of widely disparate functions by using only a few nearly identical chemical processes catalyzed by a small number of highly conserved enzymes. Reflecting on this notion may help to explain why nonspecific cancer therapeutics, which are directed at target structure instead of target function, perturb a wide array of cellular functions, thereby conferring low therapeutic indices in the clinic. A case in point is the process by which proteins are modified after translation and thereby rendered functional. In particular, prenylation, a lipid-modification process with intermediates in the cholesterol biosynthesis pathway, such as the 15-carbon farnesyl and the 20-carbon geranylgeranyl, is of great importance because Ras and other prenylated proteins, which are integrally involved in proliferative signal transduction, gain function on mutation.^2-5,9-14 The complexity of protein prenylation relates to its simplicity. That is, the existence of only three highly conserved prenyltransferases, namely FTase and geranylgeranyltransferase-I (GGTase-I) and GGTase-II, catalyze the covalent formation of a thioether bond between the prenylgroups and the thiol group of cysteines at the carboxyl terminal of a least 300 structurally and functionally disparate proteins in the human proteome.^2-4,15-20

To complicate matters even further, or maybe to simplify them, although the prenyltransferases have varying preferences for substrate proteins, FTase and GGTase-I can cross-prenylate a long list of proteins with CAAX (C = cysteine, A = aliphatic amino acid, and X = any amino acid) at their carboxy terminus.^16-21 And this capacity for cross-prenylation or redundancy is the Achilles' heel of the premise that targeting FTase alone will deleteriously affect critical cellular machinery if the intent of the therapeutic maneuver is to chiefly disrupt K-Ras and other proteins that are cross-prenylated by GGTase-I.^2-4,15-20 Herein lies the dilemma with the original rationale for developing FTase inhibitors as anticancer therapeutics. It was expected that their principal targets would be the prenylation of Ras, particularly K-Ras, which is mediated preferentially by FTase. However, GGTase-I can also prenylate K-Ras, resulting in a protein that is similarly oncogenic.^15-20 There is no question that mutated Ras, which is among the most common gain of function mutations associated with human cancer, is one of the most important strategic targets for therapeutic development against cancer.^2-4,9-12 Both wild-type and mutant Ras are synthesized as inactive cytosolic propeptides that are too hydrophilic to localize to the inner surface of the plasma membrane where they mediate signaling. Post-translational modifications of Ras, particularly the first step in this process, prenylation, which is preferentially mediated by FTase, increase the hydrophobicity of the protein, thereby facilitating association of Ras with the plasma membrane.^2-4,10-14

Effective targeting of mutant Ras, in particular mutant K-Ras, by either inhibiting Ras prenylation or perturbing other facets of Ras biology, may be therapeutically relevant for at least 30% of human cancers, especially carcinomas of the pancreas (90% K-Ras mutations), lung, and colon (approximately 30% K-Ras mutations each). However, redundancy in enzymatic function (in this case, the cross-prenylation of mutant K-Ras by GGTase-I) is the main culprit that impedes achieving this goal by targeting FTase alone.^17-20 Yet, the high probability that mutant Ras proteins would be cross-prenylated by GGTase-I after inhibition of FTase and the high likelihood that targeting mutant Ras by inhibiting FTase would not be a viable therapeutic strategy were known long before the FTase inhibitors entered the clinic.^17-20 Furthermore, even if the propensity for cross-prenylation of mutant Ras had not been known, the principal dictum of rational drug development, that biology should drive therapeutic development, would have discouraged us from evaluating the therapeutic effects of FTase inhibitors in a large number of cancer types, particularly breast cancer, in which less than 2% of tumors have Ras mutations, thereby rendering breast cancer among the lowest on the priority list of malignancies to evaluate in disease-directed clinical trials, at least based on the scientific knowledge that prevailed approximately one decade ago.^4,9,21 So, given the consistent antitumor activity observed to date and the developmental potential of the FTase inhibitors in breast cancer, leukemia, and other malignancies with low incidences of Ras mutations, if we had followed the prophets who preach the dictums of rational drug development in the face of an incomplete understanding of the biology, we would have been led even more astray than where we are today.^21-29 But, at least we are facing positive results and the prospects of further developing the FTase inhibitors for patients with breast cancer and hematologic malignancies, thereby indicating that rational clinical development paradigms are only rational if there is certainty about their rationale in the first place.

Given the urgency to translate new findings of potentially high therapeutic impact, such as the biology, relevance, and high incidence of Ras mutations in human cancer, into therapeutic advances, cancer drug development often progresses more rapidly than does an understanding of the precise mechanism of action of new agents. Because almost all structural and functional targets of cancer therapy have diverse physiologic roles, pharmacotherapeutic inhibition of almost any target usually results in a wide range of unexpected adverse effects, but on the bright side, unexpected therapeutic effects may occur as well. Furthermore, therapeutic manipulations may confer preferential tumor growth inhibition in certain cancers, which, given the complexity of the living cell and our current state of ignorance about cancer biology, cannot be predicted a priori. Unfortunately, clinical evaluations are the only way to truly gauge the potential of most novel, rationally designed, target-based therapeutics at this time. With regard to the FTase inhibitors, to quote the Rolling Stones, prophets to some of the current generation of cancer researchers, "you can't always get what you want [ie, activity against K-Ras–driven tumors by FTase inhibition], but if you try sometimes, you might find you get what you need [such as antitumor activity against some other unexpected tumor type, such as breast cancer, as a result of FTase inhibition of an unknown target]."

Nevertheless, ignorance is no excuse for building houses of cards, especially if cancer patients are the cards, and wholehearted efforts must be made to assess the integrity of the foundation on which we develop new cancer therapeutics in a real-time, iterative fashion. Just as important, we must be prepared to abandon our presumptions about the mechanism of action and rational development pathways of new therapeutics as we put our best foot forward. In retrospect, if we had fastidiously paid attention to whether the intended target of the FTase inhibitors, K-Ras itself, was sufficiently inhibited in patients receiving treatment early in the course of developing the FTase inhibitors, perhaps drug development evaluations would not have gone so far astray as they did go with the FTase inhibitors,^29-33 and what a long strange trip it's been! And, perhaps, if this issue had been addressed sooner and with rigor, we might have been much further along in evaluating the merits of the FTase inhibitors in treating breast cancer, leukemia, myelodysplasia, and who knows what else. Let's not forget about the hefty resources expended in large, randomized, phase III trials of the FTase inhibitors in patients with colorectal and pancreatic cancers.^29-33 The rationale for these evaluations, which failed to demonstrate any clinical benefit when the FTases were added to standard therapy, was supported neither by evidence that the agents inhibit K-Ras prenylation or protein function nor by encouraging signals in earlier studies in these tumor types.

After the peptidomimetic FTase inhibitor L778,123 failed to demonstrate antitumor activity in a few small phase II trials in cancers with high incidences of Ras mutations, the sponsor halted its further development and later disclosed that L778,123 was actually developed as a dual, albeit critically balanced, inhibitor of both FTase and GGTase-I.^34-36 Because L778,123 was principally developed to robustly inhibit K-Ras, the rationale for the agent's design now makes a lot of sense, but its capacity to inhibit GGTase-I, in addition to FTase, was unbeknownst to investigators during its early development.^34-36 To support the clinical development of L778,123, pharmacodynamic assays using peripheral-blood mononuclear cells to measure the inhibition of prenylation of HDJ2 and Rap1A, which are proteins that are FTase and GGTase-I substrates, respectively, as well as K-Ras prenylation, were validated in animal models and incorporated into early clinical trials.³⁶ At the maximum-tolerated dose of L778,123 administered as a protracted continuous infusion, prenylation of both HDJ2 and Rap1A was inhibited, indicating that the agent was capable of inhibiting both FTase and GGTase-I, but the intended target of the drug, K-Ras, was not at all perturbed.³⁶ Despite not knowing the precise mechanism responsible for the toxicities that precluded dose escalation of L778,123, it was clear that the magnitude of inhibition of both FTase and GGTase-I required to induce total blockade of K-Ras prenylation and function would also induce a potpourri of serious adverse effects.³⁶ Although the sponsor should be commended on its decision to incorporate these elegant studies into the clinical development of L778,123 to address root questions, the final answers of which provided a logical explanation of why the agent failed to target Ras, the unique properties of L778,123 were not disclosed to the scientific community at large, let alone investigators, until long after many efforts with other FTase inhibitors directed against cancers with a high incidence of Ras mutations failed, along with precious human and financial resources.^29-33

The phase I and II efforts of Sparano et al¹ in evaluating the feasibility and activity of the FTase inhibitor tipifarnib and chemotherapy in the neoadjuvant treatment of breast cancer, as reported in this issue, were built on the original findings of other investigators,^19,22,24 whose reports of 10% to 14% objective response rates and a respectable degree of clinical benefit in previously treated patients with advanced breast cancer, a once-presumed totally illogical tumor type to study based on its low incidence of mutant Ras, humbled the burgeoning field of rational cancer drug development. Clinician-scientists, who abhor an explanation vacuum, immediately espoused alternate hypotheses, such as increased signaling by aberrant human epidermal growth factor receptor 2, to explain the clinical results and fill the void; others advocated that erbB receptors are mediated through Ras.^19,22,24 However, the antitumor activity of the FTase inhibitors in breast cancer was independent of the status of Ras, human epidermal growth factor receptor 2/epidermal growth factor receptor, and estrogen/progesterone receptors, which has also been supported by the findings of Sparano et al.^1,21,22,24 It seems that inhibition of virtually all of the 300 or so farnesylated proteins has prevailed at one time or another as the principal explanation to account for the Ras-independent activity of the FTase inhibitors ever since the perplexing positive studies in breast cancer and hematologic malignancies were reported.^3,37 Just some of the many favorite farnesylated proteins, which have been offered up to explain away these paradoxical efficacy results, include wild-type Ras, RhoB and other Rho proteins, RheB, component(s) of the phosphoinositide 3' kinase/serine/threonine kinase Akt-2 pathway, and the kinetochore-binding centromere proteins E and F. However, definite proof that inhibition of these proteins is involved in the mechanism of antitumor activity of the FTase inhibitors is greatly lacking.^3,37 Nevertheless, it is clear that we know little about how FTase inhibitors work and why some tumors, but not others, respond, and there is little doubt that enhancing our knowledge of the mechanism by which these agents inhibit cell proliferation and induce apoptosis will facilitate the optimal development of the FTase inhibitors and benefit cancer patients. In fact, the toxicity profile of the dose-dense AC plus tipifarnib regimen reported by Sparano et al,¹ which is similar to that observed for dose-dose AC alone, suggests that tipifarnib, albeit modestly active as monotherapy, allows for the concurrent administration of AC without compromising the relevant dose and schedule of the other agents, which is particularly important in a potentially curative neoadjuvant setting. Still, elucidating the precise mechanism of the FTase inhibitors may facilitate selection of optimal regimens for development, not to mention the optimal means to select patients who might benefit most from the addition of this class of new agents to our therapeutic armamentarium. Furthermore, a detailed knowledge of the precise mechanism of action of the FTase inhibitors can enable the development of more specific inhibitors with greater therapeutic potential against malignant, as well as nonmalignant, diseases, such as those caused by infectious agents such as Plasmodium falciparum (malaria), Trypanosome bruecei (African sleeping sickness), and hepatitis delta virus (hepatitis), which exploit host FTase in key aspects of their own life cycle.³⁸

Sparano et al¹ have joined the ranks of many other investigators who have shown that the FTase inhibitors are capable of inhibiting FTase in tumors, and a proclamation decreeing that no further proof of this action need be rendered is forthcoming. Instead, the question is: What differentiates the constituents of tumors of responding patients from nonresponders? Because treatment with FTase inhibitors blocks protein farneyslation in the tumors of both responders and nonresponders alike, the answer to this question likely relates to specific oncogenic or critical proteins, which require farnesylation for functionality in responding tumors. The answer may be ascertained by assaying the prenylation pattern of proteins in a sufficient number of tumor samples from patients undergoing treatment with FTase inhibitors, preferably in phase II and III studies involving a sensitive tumor type. The pathologic complete response rate of 33% reported by Sparano et al¹ exceeds the threshold rate of 15% defined a priori for proceeding to the next stage of a the study, which is an ideal setting for these investigators to answer this question. In addition to ascertaining further information about the clinical merits of the AC-tipifarnib regimen, the neoadjuvant setting is perhaps the ideal clinical setting to address how new agents induce antineoplastic activity because of the feasibility of sampling tumors before and after treatment.

The aforementioned proposal should not be construed as merely an academic exercise because it may bring us closer towards the home stretch of the long strange trip with the FTase inhibitors, which currently seem to be only modestly active in a small proportion of, as of yet unknown, patients. Elucidation of the precise farnesylated protein whose targeting by FTase inhibitors directly relates to drug activity can also lead to a new generation of more potent, highly specific FTases inhibitors using state of the art drug design technology and combinatorial screening. Similar to deadheads, who relentlessly pursue remnants of their idols, the Grateful Dead, to the four corners of the galaxy, we should back up a bit and begin to reformulate alternate strategies to relentlessly pursue Ras as a target for therapeutic development against cancer because Ras was the initial starting point of this long strange trip.

Author's Disclosures of Potential Conflicts of Interest

The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Eric K. Rowinsky ImClone Systems Inc (N/R) Johnson & Johnson (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

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