Rossitza Gueorguieva Alargova

Abstract 4693: The selective ERK inhibitor BVD-523 is active in models of MAPK pathway-dependent cancers, including those with intrinsic and acquired drug resistance

The MAPK (RAS-RAF-MEK-ERK) pathway is activated in many cancers, and the clinical efficacy of BRAF and MEK inhibitors in melanoma confirms that targeting the MAPK pathway has therapeutic potential. Unfortunately, intrinsic and acquired drug resistance limits use of MAPK-directed therapies, and resistance is often associated with activated ERK signaling. Here, we report characterization of BVD-523 (ulixertinib), a novel small-molecule ERK1/2 kinase inhibitor currently under investigation in Phase 1 clinical trials. BVD-523 potently and selectively inhibits ERK1 and ERK2 kinases in a reversible, ATP-competitive fashion. Consistent with its mechanism of action, BVD-523 inhibits signal transduction, cell proliferation, and cell survival, most potently in cell lines bearing mutations that activate MAPK pathway signaling. Similarly, single-agent BVD-523 inhibits tumor growth in vivo in BRAF-mutant melanoma and colorectal xenografts as well as in KRAS-mutant colorectal and pancreatic models. Combination treatment with BVD-523 and dabrafenib inhibits tumor growth in a BRAF-mutant melanoma model. Importantly, BVD-523 is effective in several models that show intrinsic or acquired resistance to other MAPK pathway inhibitors. BVD-523 inhibits with equivalent potency the growth of parental cells or those cultured for resistance to dabrafenib, trametinib, or the combination of both drugs. Additionally, BVD-523 inhibits growth in wild-type cells and a RAF/MEK cross-resistant cell line bearing a MEK1 Q56P mutation with similar potency. Lastly, single-agent BVD-523 inhibits the growth of a patient-derived tumor xenograft harboring cross-resistance to dabrafenib, trametinib, and the combination treatment following clinical progression on a MEK inhibitor. Phase 1 trials of BVD-523 are currently recruiting patients with advanced solid tumors (NCT0178429) or hematologic malignancies (NCT02296242). Eligibility criteria include diagnosis according to certain genetic features, and treatment in backgrounds including progression following prior MAPK targeted therapy. The primary objective of these studies is to identify the recommended Phase 2 dose(s) for single-agent BVD-523 treatment. Additional objectives include pharmacokinetic and pharmacodynamic assessments, and preliminary measures of efficacy. The solid tumor protocol has met its study objectives in Part 1 (defining the safety profile and maximum tolerated dose), and will be reported separately; findings appear consistent with the activity profile defined in preclinical studies. In total, preclinical and clinical studies will help elucidate how BVD-523 (ulixertinib) may be used as a novel agent in MAPK-directed therapeutic strategies, including for patients that have failed treatment due to intrinsic or acquired resistance and active signaling through ERK. Citation Format: Ursula Germann, Brinley Furey, Jeff Roix, William Markland, Russell Hoover, Alex Aronov, Michael Hale, Guanjing Chen, Gabriel Martinez-Botella, Rossitza Alargova, Bin Fan, David Sorrell, Kay Meshaw, Paul Shapiro, Michael J. Wick, Cyril Benes, Mathew Garnett, Gary DeCrescenzo, Mark Namchuk, Saurabh Saha, Dean J. Welsch. The selective ERK inhibitor BVD-523 is active in models of MAPK pathway-dependent cancers, including those with intrinsic and acquired drug resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4693. doi:10.1158/1538-7445.AM2015-4693

Abstract 3674: Pentarins: Improved tumor targeting through nanoparticle encapsulation of miniaturized biologic drug conjugates

The specific targeting of cytotoxic drugs to solid tumors has achieved success with the advent of antibody drug conjugates (ADCs). This approach has had notable success but has also met with limitations. The most common issue limiting ADC effectiveness is believed to be low tumor permeation by these large (∼150 kDa) molecules. Attempts to address this limitation have been focused on the design of miniaturized biologic drug conjugates such as those with small protein or small molecule targeting moieties. However, these efforts uniformly result in conjugates with poor pharmacokinetics in contrast to the extended plasma pharmacokinetics observed with ADCs. The Pentarin platform encapsulates miniaturized biological drug conjugates within nanoparticles to improve the biodistribution of these classes of conjugates. There are multiple benefits to this strategy. Through the enhanced permeability and retention (EPR) effect the nanoparticles accumulate in the perivascular space of the tumor tissue. Next the nanoparticles release the permeable miniaturized conjugate that can penetrate in to the tumor, bind to an over-expressed target on the cancer cell surface, internalize the payload and elicit a strong biological effect. All of this is further enhanced by the extended plasma pharmacokinetics of the nanoparticle when compared to the conjugate alone. To exemplify the Pentarin platform we have designed novel miniaturized biologic drug conjugates to an over-expressed target found in small cell lung cancer. In vitro data has shown the designed conjugates specifically and potently target tumor cells expressing the receptor of interest. When encapsulated in nanoparticles, these miniaturized biologic drug conjugates have improved plasma pharmacokinetics, the amount of payload delivered to xenograft tumors is increased and the xenograft efficacy is significantly more pronounced over drug conjugate not in a nanoparticle. These observations correlate with in vivo mechanistic assays in the xenograft tissue. These data will be presented, together with the name of the target, to demonstrate the impact of the Pentarin platform and to show progress towards the first clinical candidate from this work. Citation Format: Mark T. Bilodeau, Rajesh Shinde, Brian White, Patrick Bazinet, Kerry Whalen, Michelle Dupont, Kristina Kriksciukaite, Jamie Quinn, Beata Sweryda-Krawiec, Rossitza Alargova, Adam Brockman, Patrick Lim Soo, Kristan Meetze, Benoit Moreau, Haley Oller, Mike Ramstack, Danielle Rockwood, Sukhjeet Singh, Tsun Au Yeung, Sudha Kadiyala, Craig Dunbar, Richard Wooster. Pentarins: Improved tumor targeting through nanoparticle encapsulation of miniaturized biologic drug conjugates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3674. doi:10.1158/1538-7445.AM2015-3674

Abstract 39: Discovery of PEN-221, an SSTR2-targeting maytansinoid conjugate with potent activity in vitro and in vivo

Here we describe the discovery and the structure of PEN-221, a somatostatin receptor 2 (SSTR2) targeting peptide conjugated to DM1. PEN-221 is the first clinical compound from Tarveda’s Pentarin platform, which utilizes miniaturized drug conjugates that diffuse rapidly and deeply into solid tumors. Antibody drug conjugates (ADCs) have garnered a significant amount of attention in their ability to direct cytotoxic drugs to cancer cells; however, the efficacy of ADCs in solid tumors is limited by the slow diffusion of such large molecules through solid tumor tissue. Pentarins are designed to improve the efficacy of targeted therapies through effective tumor cell targeting and enhanced tumor penetration. SSTR2, a GPCR overexpressed in multiple types of neuroendocrine tumors, including small cell lung cancers, internalizes rapidly upon agonist stimulation, making it an ideal vector for delivering cytotoxic payloads. Examination of a variety of SSTR2 targeting ligands, as well as several potential conjugation sites, led to the identification of the C-terminal side chain of [Tyr3]-octreotate amide as the best conjugation site for a lipophilic payload. The use of DM1 as a payload afforded superior receptor affinity and receptor internalization when compared to other similarly potent microtubule-targeting agents. In vitro studies show that PEN-221 has receptor-dependent cytotoxic effects, and preclinical studies demonstrate PEN-221 induces tumor regression in several SSTR2 expressing xenograft models. Citation Format: Brian H. White, Patrick Bazinet, Kerry Whalen, Michelle DuPont, James M. Quinn, Rossitza Alargova, Tsun Au Yeung, Adam Brockman, James Gifford, Haley Oller, Kristina Kriksciukaite, Charles-Andre Lemelin, Patrick Lim Soo, Benoit Moreau, Samantha Perino, Gitanjali Sharma, Rajesh Shinde, Beata Sweryda-Krawiec, Mary Simcox, Richard Wooster, Mark T. Bilodeau. Discovery of PEN-221, an SSTR2-targeting maytansinoid conjugate with potent activity in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 39. doi:10.1158/1538-7445.AM2017-39

Abstract 4484: BTP-114: An albumin binding cisplatin prodrug with improved and sustained tumor growth inhibition

Platinum drugs have proven to be effective in treating cancer, for example >90% of men with testicular cancer are cured with a platinum therapeutic. Platinum drugs are also widely used for the adjuvant treatment of common cancers such as those of the lung, colon and ovary. However for the majority of tumor types the clinical response rates for platinum therapies are low, for example the 1 year survival rate for lung cancer patients treated with platinum therapeutics is ∼30%. The key limitations of the existing platinum therapies are the dose limiting toxicities that restrict dose and/or duration of therapy and the absence of personalization that targets the drugs to the patients most likely to benefit. To address these issues we have designed a novel prodrug of cisplatin, BTP-114. On infusion into the blood a maleimide group on BTP-114 covalently attaches to serum albumin. This prolongs the circulation of BTP-114 in plasma and alters the biodistribution of the compound. Importantly the dose of platinum can be increased and the amount of platinum that accumulated in xenograft tumor tissue and the amount of platinum bound to tumor DNA are both increased relative to cisplatin. An elevation of DNA damage in tumor cells in vivo is observed with BTP-114. Together the properties of BTP-114 result in pronounced and sustained tumor growth inhibition compared to cisplatin. In parallel to the discovery of BTP-114 we have explored potential biomarkers to predict which tumors are most likely to respond. These data will be presented towards developing BTP-114 as a personalized platinum medicine for cancer patients. BM and RA contributed equally to this work. Citation Format: Benoit Moreau, Rossitza Alargova, Adam Brockman, Kerry Whalen, Jamie Quinn, Kristan Meetze, Patrick Bazinet, Michelle DuPont, Beata Krawiec, Kristina Kriksciukaite, Charles Lemelin, Patrick LimSoo, Haley Oller, Mike Ramstack, Danielle Rockwood, Rajesh Shinde, Sukhjeet Singh, Brian White, Tsun AuYeung, Craig Dunbar, Mark Bilodeau, Richard Wooster. BTP-114: An albumin binding cisplatin prodrug with improved and sustained tumor growth inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4484. doi:10.1158/1538-7445.AM2015-4484