Improving the Armamentarium of PI3K Inhibitors with Isoform-Selective

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IN THE SPOTLIGHT Improving the Armamentarium of PI3K Inhibitors with Isoform-Selective Agents: A new Light in the Darkness Jordi Rodon 1 and Josep Tabernero 2 Summary: Excitement and drug-development efforts aimed at targetable genetic aberrations in the PI3K/AKT/ mTOR pathway have declined due to the limited clinical performance of these inhibitors as monotherapies. New, more isoform-selective treatments, such as taselisib, promise to both expand the therapeutic window and increase efﬁ cacy. Cancer Discov; 7(7); 666–9. ©2017 AACR.

See related article by Juric et al., p. 704 (10).

That the PI3K pathway plays a relevant role in cancer, as rush” including the one promised by immuno-oncology, and one of the most frequently activated pathogenic signaling closed many PI3K inhibitor development programs ( Table 1 ). routes in human cancers, has been known for decades (1 ). In breast cancer, for example, one of the most promising areas A large body of literature has been compiled in this fi eld, for the development of PI3K inhibitors, positive results with and the PanCancer analysis of The Cancer Genome Atlas mTOR or PI3K inhibitors in hormone-sensitive disease seem just confi rmed that a multitude of alterations are frequently to now be eclipsed by the shining cyclin-dependent kinase present in many tumor types (2 ), including mutations and/ inhibitors, which have unquestionable antitumor effi cacy, or amplifi cation of PIK3CA, AKT1-3, and PTEN or INPP4B. have side effects manageable in a busy clinic, and require no These alterations are known to induce a transformed phe- intricate predictive markers. notype and drug resistance and consequently pose PI3K Looking back to 2012, when more than 30 drugs targeting pathway components as attractive targets for anticancer drug different nodes of the PI3K pathway were in clinical develop- development. Structural studies of PI3K enzymes and medici- ment, if we now revisit the open questions of that time (many nal chemistry efforts enabled the development of suffi ciently phase I trials of these drugs already were completed by then), specifi c drugs with favorable drug properties to suggest that many of them still remain unsolved today. To name but a few: their development could become another archetype in preci- (i) Which of the different agents, whether mTOR, AKT, sion medicine ( 1 ). Drug development searching for inhibiting pan-PI3K, or isoform-specifi c PI3K inhibitors, provide nodes of the PI3K pathway blossomed and brought an onrush the greatest therapeutic index? Is there a specifi c genetic of drug companies seeking to regulate this pleiotropically context that prognosticates superior activity for each altered pathway. In this urgency to hit the market, data indi- class? cating the complexity of PI3K signaling, redundancies, and (ii) What magnitude of signaling inhibition is required to cross-talk with other pathways capitulated to the need for produce biological (apoptosis) and clinical effects? If oversimplifi cation of conventional clinical trials (which can chronic inhibition at that level is not sustainable due answer only a limited number of simple questions). Evidence to side effects (either off-target effects or insuffi cient challenging the paradigm of PIK3CA mutations behaving as control of on-target toxicities), is intermittent dosing a classic oncogene addiction scenario was neglected, while suffi cient to achieve the desired effect? results of the next blockbuster were to be anticipated. When (iii) If there are redundant components of the pathway and only one regulatory approval of one such agent, idelalisib compensatory intrapathway or extrapathway mecha- (Gilead Sciences) was achieved (in several hematologic malig- nisms of resistance, which combinations would make nancies), the gold fever vanished with a therapeutic ice bath. sense in cancer patients (rather than in artifi cial in Following the explosion in drug development, an implosion: vitro/ in vivo models)? Pharma companies moved on, in pursuit of the next “gold (iv) Which patients, selected on the basis of which biomarkers, are more likely to benefi t from these agents? 1 Investigational Cancer Therapeutics, The University of Texas MD Ander- Nowadays, though, some progress has actually shed light in 2 son Cancer Center, Houston, Texas. Medical Oncology Department, Vall this fi eld, albeit away from the fuss of harsh industrial compe- d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. tition, and new insights are providing a deeper understanding of the pathway and its pharmacology. Such discovery may corresponding Author: Jordi Rodon , Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 ultimately deliver on the full potential of PI3K inhibitors. On Holcombe Boulevard, Houston, TX 77030. Phone : 713-792-5603; E-mail: one hand, pharmacologic research is following two natural [email protected] paths to overcome some of the toxicity observed with pan-PI3K doi: 10.1158/2159-8290.CD-17-0500 inhibitors (and these are not mutually exclusive solutions): © 2017 American Association for Cancer Research. to explore new scheduling alternatives that may be less toxic

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Table 1. Drugs inhibiting the PI3K/AKT/mTOR pathway that were in early clinical stages in 2012 and their current status

Drug Company Target(s) Status in 2012 Current status a PI3K–mTOR inhibitors Wortmannin PI3K, mTOR, DNA-PK, MAPK Preclinical Discontinued (NVP)-BGT226 Novartis PI3K, mTOR Phase I Discontinued (NVP)-BEZ235/dactolisib Novartis PI3K, mTOR Phase I, II Discontinued XL765/SAR254409/voxtalisib Exelixis/Sanofi -Aventis PI3K, mTOR Phase I Discontinued GDC-0980/apitolisib Genentech PI3K, mTOR Phase I Discontinued PI-103 Piramed Pharma/Roche PI3K, mTORC1/2, DNA-PK Preclinical Discontinued GSK1059615 GlaxoSmithKline PI3K, mTOR, DNA-PK Phase I Discontinued PKI-587/PF-05212384/gedatolisib Pfi zer PI3K, mTOR Phase I Active (2 trials) PF-04691502 Pfi zer PI3K, mTOR Phase I Discontinued Pan-PI3K inhibitors (NVP)-BKM120/buparlisib Novartis PI3K Phase I, II No further active development LY294002 Lilly PI3K, other related kinases Preclinical Discontinued SF1126 Semafore PI3K and mTOR Phase I Discontinued PWT-458 Wyeth/Pfi zer PI3K Preclinical Discontinued PX-866 Oncothyreon Inc. PI3K Phase I Discontinued XL-147/SAR245408/pilaralisib Exelixis/Sanofi -Aventis PI3K Phase I Discontinued ZSTK474 Zenyaku Kogyo Co. Ltd. PI3K Preclinical Discontinued GSK615/GSK1059615 GlaxoSmithKline PI3K Phase I Discontinued CH5132799 Chugai Pharma Europe Ltd. PI3K Phase I Discontinued GDC-0941/pictilisib PIramed Pharma/Genentech PI3K, FLT3 Phase I Discontinued BAY 80-6946/copanlisib Bayer PI3K Phase I Active (10 trials) Isoform-specifi c PI3K inhibitors CAL-101/idelalisib Calistoga Pharmaceuticals PI3K (p110δ) Phase I Approved BYL719/alpelisib Novartis PI3K (p110α) Phase I Active (17 trials) INK1117/TAK-117/ Intellikine/Millennium PI3K (p110α) Phase I Active (1 trial) serabelisib Pharmaceuticals AS-252424 Merck Serono PI3K (p110γ) Preclinical Discontinued GSK2636771 GlaxoSmithKline PI3K (p110β) Phase I Active (14 trials) TGX-221 Alexis/Enzo Life Sciences PI3K (p110β) Preclinical Discontinued Inc. GDC0032/taselisib Genentech PI3K (p110α, δ, γ) Phase I Active (5 trials) AKT inhibitors Perifosine/KRX-0401 AEterna Zentaris Inc./Keryx AKT, MEK 1/2, ERK 1/2, JNK Phase I, II Discontinued Biopharmaceuticals Triciribine/API-2 VioQuest Pharmaceuticals AKT 1, 2, 3 Phase I Active (3 trials) GDC-0068/ipatasertib Roche/Genentech AKT 1, 2, 3 Phase I Active (2 trials) SR13668 SRI International AKT Preclinical Discontinued AR-67/DB-67 Arno Therapeutics AKT Phase I, II Discontinued AR-42 Arno Therapeutics AKT Preclinical Discontinued GSK690693 GlaxoSmithKline AKT 1, 2, 3 Phase I Discontinued KP372-1 QLT Inc. AKT, PDK1, FLT3 Preclinical Discontinued VQD-002/API-2 VioQuest Pharmaceuticals AKT Phase I, II Discontinued A-443654 Abbott Laboratories AKT Preclinical Discontinued XL-418 Exelixis AKT/p70 S6K Phase I Discontinued MK-2206 Merck AKT 1, 2, 3 Phase I Active (2 trials) TORC1 inhibitors (rapalogs) Rapamycin/sirolimus Wyeth/Pfi zer mTORC1 Phase I, II Approved CCI-779/temsirolimus Wyeth/Pfi zer mTORC1 Phase I, II Approved RAD001/everolimus Novartis mTORC1 Phase I, II Approved AP-23573/ridaforolimus/ Ariad/Merck mTORC1 Phase I, II No further active deforolimus development

(continued)

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Table 1. Drugs inhibiting the PI3K/AKT/mTOR pathway that were in early clinical stages in 2012 and their current status (Continued)

Drug Company Target(s) Status in 2012 Current status a TORC1/2 inhibitors AZD-8055 AstraZeneca mTORC1/mTORC2 Phase I, II Discontinued AZD2014 AstraZeneca mTORC1/mTORC2 Phase I, II Active (29 trials) OSI-027 OSI Pharmaceuticals mTORC1/mTORC2 Phase I Discontinued INK-128/MLN0128/TAK228 Intellikine mTORC1/mTORC2 Phase I Active (17 trials) PP-242 UCSF mTORC1/mTORC2 Phase I Discontinued CC-223 Celgene mTORC1/mTORC2, DNA-PK Phase I Active (1 trial)

Abbreviations: DNA-PK, DNA-dependent protein kinase; FLT3, Fms-like tyrosine kinase 3. a As per ClinicalTrials.gov and http://adisinsight.springer.com/ accessed May 2017. and to develop isotype-specifi c PI3K inhibitors with different, both sustaining residual downstream mTORC1 activity maybe better, specifi city and safety profi les, including isoform- and indicating a need for potent downstream inhibition. specifi c, or “isoform-balanced” (idelalisib - PI3Kδ, alpelisib - • Second-generation drugs, such as the PI3Kα-specifi c PI3Kα, copanlisib - PI3Kα/δ, taselisib - PI3Kα/δ/γ…). On the inhibitors alpelisib and serabelisib, show better safety other, the molecular biology of the pathway is being explored profi les and probably an increased antitumor effi cacy in novel ways. Translational research using new research para- compared with what was previously seen in ER-positive digms, models, methods, and tools such as patient-derived xeno- breast cancer (patients with PIK3CA mutation treated grafts, cell-free DNA, and warm autopsies has certainly helped with alpelisib had a disease control rates of 53% in mon- in these efforts. Through these new approaches in molecular otherapy and 80% in combination with antihormonal biology, we are achieving (i) a better understanding of the role therapy; ref. 9 ). of PI3K and the different isoforms, their signaling and redun- In this new context, Juric and colleagues ( 10 ) present the dant wiring as well as the potency needed for antitumor effect; results of taselisib, a “p110β-sparing” PI3K inhibitor. In a (ii) knowledge of how PI3K isoforms and family components way, it leverages some of this knowledge and represents one contribute to other hallmarks of cancer, such as metabolism, of the members of the third wave of drug development of inﬂ ammation, angiogenesis, and immunosurveillance; and (iii) PI3K inhibitors (if rapalogs represent the fi rst and PI3K/ discerning the role of heterogeneity and clone evolution, and mTORC/AKT inhibitors embody the second). Some results how they may drive secondary resistance (3 ). Let us take breast may not be especially novel, such as their safety profi le or cancer, for instance, and delineate some of the advancements pharmacodynamic markers. The observed side effects are driven by translational research: well known in this drug family and probably explained as • Our understanding of the cross-talk between estrogen a class effect (colitis expected from PI3K γ inhibition, hyper- receptor (ER) and PI3K has certainly improved. Recogniz- glycemia from PI3Kα inhibition). Results from biomarkers ing that PI3K pathway alterations in hormone-sensitive such as surrogate tissues, metabolic markers, and FDG-PET tumors act as resistance mechanisms to antiestrogen thera- scan confi rm prior observations with other PI3K inhibitors. pies, we now know that both pathways are interdependent Neither of these (safety observations or pharmacodynamic and dual inhibition is needed in any case, even in PIK3CA markers) greatly illuminates the role of the different isoforms wild-type cases (4 ). This could be achieved with different (one wonders whether at the recommended doses, p110β schedules of pharmacologic inhibition that, although all is indeed “spared”). The antitumor effects are however very effi cacious, may have different pharmacodynamic effects intriguing. In hormone-sensitive breast cancer, and especially and therapeutic index (5 ). in PIK3CA-mutant tumors, both taselisib and alpelisib seem • Clonal evolution in ER-positive breast cancer and emer- to be achieving signifi cant antitumor effect as monotherapy, gence of PIK3CA mutations seems important as a predictive and even more so in combination with antihormone therapy. biomarker: In a phase III study of buparlisib (a pan-PI3K These “new kids on the block” are showing signifi cant prom- inhibitor) in ER-positive, HER2-negative advanced breast ise, and this is well exemplifi ed here by the trial of Juric and cancer, patients with PIK3CA -mutant status detected in colleagues. Considering the new body of emerging evidence, circulating tumor DNA performed poorly on fulvestrant a second wave of clinical research and drug development with alone, but obtained benefi t from the addition of the PI3K PI3K inhibitors is to be expected. It is time for science again, inhibitor to the regimen (6 ). and to let translational research do the talking. • On -treatment biopsies and warm autopsies upon progres- sion can also help in depicting secondary mechanisms of Disclosure of Potential conﬂ icts of Interest resistance in this fi eld. Of the multiple mechanisms of J. Rodon reports receiving commercial research grants from Bayer primary resistance described in in vitro/ in vivo models, in and Novartis and is a consultant/advisory board member for Ability, clinical samples secondary mutations in PTEN (7 ) and/or Novartis, Orion, and Peptomyc. J. Tabernero is a consultant/advisory increased PDK1–SGK1 signaling (8 ) have been observed, board member for Genentech and Novartis.

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Grant Support 6. Baselga J, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, et al. Abstract S6-01: PIK3CA status in circulating tumor DNA (ctDNA) predicts The University of Texas MD Anderson Cancer Center is supported efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmeno- by the NIH Cancer Center support grant CA016672. pausal women with endocrine-resistant HR+/HER2− advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 Published online July 6, 2017. trial. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8–12; San Antonio, TX. Philadelphia, PA: AACR; 2015. Abstract nr S6-01. References 7. Juric D, Castel P, Griffith M, Griffith OL, Won HH, Ellis H, et al. . 1 Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K Convergent loss of PTEN leads to clinical resistance to a PI(3)Kalpha inhibitors: lessons learned from early clinical trials. Nat Rev Clin inhibitor. Nature 2015;518:240–4. Oncol 2013;10:143–53. 8. Castel P, Ellis H, Bago R, Toska E, Razavi P, Carmona FJ, et al. PDK1- 2. Tamborero D, Gonzalez-Perez A, Perez-Llamas C, Deu-Pons J, Kan- SGK1 signaling sustains AKT-independent mTORC1 activation and doth C, Reimand J, et al. Comprehensive identification of mutational confers resistance to PI3Kalpha inhibition. Cancer Cell 2016;30:229–42. cancer driver genes across 12 tumor types. Sci Rep 2013;3:2650. 9. Janku F, Juric D, Cortes J, Rugo H, Burris HA, Schuler M, et al. 3. Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Abstract PD5-5: Phase I study of the PI3Kα inhibitor BYL719 plus cancer: impact on tumor cells, their protective stroma, angiogenesis, fulvestrant in patients with PIK3CA-altered and wild type ER+/ and immunotherapy. Cancer Discov 2016;6:1090–105. HER2− locally advanced or metastatic breast cancer. In: Proceedings 4. Bosch A, Li Z, Bergamaschi A, Ellis H, Toska E, Prat A, et al. PI3K inhibi- of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Can- tion results in enhanced estrogen receptor function and dependence in cer Symposium: 2014 Dec 9–13; San Antonio, TX. Philadelphia, PA: hormone receptor-positive breast cancer. Sci Transl Med 2015;7:283ra51. AACR; 2014. Abstract nr PD5-5. 5. Yang W, Hosford SR, Dillon LM, Shee K, Liu SC, Bean JR, et al. 10. Juric D, Krop I, Ramanathan RK, Wilson TR, Ware JA, Sanabria Strategically timing inhibition of phosphatidylinositol 3-kinase Bohorquez SM, et al. Phase I dose-escalation study of taselisib, an to maximize therapeutic index in estrogen receptor alpha-positive, oral PI3K inhibitor, in patients with advanced solid tumors. Cancer PIK3CA-mutant breast cancer. Clin Cancer Res 2016;22:2250–60. Discov 2017;7:704–15.

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Jordi Rodon and Josep Tabernero

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