City of Hope Scientists Highlight New Findings at AACR 2021

On April 9, 2021 City of Hope, a world-renowned cancer research and treatment center, reported that it will showcase breakthrough research and innovative studies at the first week of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021, which will take place virtually from April 10 to 15 (Press release, City of Hope, APR 9, 2021, View Source [SID1234577802]).

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City of Hope scientists will present findings that could one day lead to an effective KRAS inhibitor for solid tumors, innovative chimeric antigen receptor (CAR) T cell therapy for glioblastoma, potent CAR natural killer cell therapy against pancreatic cancer, improved health equity for marginalized communities, better ways to prevent and treat colorectal cancer, and much more.

The multidisciplinary meeting program will highlight the best cancer science and medicine in the world. Last year more than 73,000 people from 140 countries attended AACR (Free AACR Whitepaper)’s first-ever virtual meeting. Some City of Hope research that will be presented at the AACR (Free AACR Whitepaper) meeting is highlighted below.

More competition in KRAS inhibitor space: Revolution Medicine’s RMC-4630
Time: April 10 from 2:05 to 2:15 p.m. EDT
This late-breaking oral presentation led by City of Hope’s Marianna Koczywas, M.D., will address the anti-tumor activity and tolerability of the SHP2 inhibitor RMC-4630 as a single agent in patients with RAS-addicted solid cancers. The first-in-human Phase 1 study demonstrated that RMC-4630 is a potent, selective inhibitor of SHP2, which appears to be an important regulator of growth signals for cancer cells. RMC-4630 exhibited anti-tumor activity in cancers harboring KRASG12C, KRASG12D, NF1 loss of function and BRAF Class 3 mutations. Based on these findings, four targeted therapy combination studies are currently underway, including combinations of RMC-4630 with the KRASG12C inhibitor sotorasib, the checkpoint inhibitor pembrolizumab and the MEK inhibitor cobimetinib.

CAR T cell therapy reshapes tumor microenvironment in glioblastoma
Time: April 12 from 2:05 to 2:15 p.m. EDT
This translational research uses murine models and patient samples to evaluate how CAR T cell therapy reshapes the tumor microenvironment to promote host anti-tumor immune responses in glioblastoma. Christine Brown, Ph.D., deputy director of the T Cell Therapeutics Research Laboratory at City of Hope, and her colleagues look at IL13Rα2-targeted CAR T cells for the treatment of glioblastoma and demonstrate that CAR T cell treatment of mice with glioblastoma alters the tumor immune landscape, activates myeloid cells within tumors and induces innate T cell memory responses. These studies establish that CAR T cell therapy has the potential to reshape the microenvironment of solid tumors, potentially activating innate, adaptive immunity. Cancer Discovery recently accepted this research for publication.

CAR NK therapy directed against pancreatic cancer
Time: April 10, 8:30 a.m. to 11:59 p.m. EDT
This late-breaking poster presentation led by City of Hope’s Michael Caligiuri, M.D., and Jianhua Yu, Ph.D., presents a potent human chimeric antigen receptor (CAR) natural killer (NK) cell therapy against pancreatic cancer. About 60-80% of pancreatic cancer express prostate stem cell antigen. The scientists developed CYTO NK-203 to spontaneously kill both liquid and solid tumors in animal models using human umbilical cord NK cells that are transduced with CAR. The research suggests that this biopharmaceutical may be able to prolong survival against pancreatic tumor cells without side effects, at least in animal models. CYTO NK-203, which was licensed to CytoImmune Therapeutics Inc., is expected to move into clinical trials at City of Hope within 12 months, Caligiuri said.

Neighborhood disadvantage linked to aggressive non-small cell lung cancer
Time: April 10 from 8:30 a.m. to 11:59 p.m. EDT
City of Hope’s Loretta Erhunmwunsee, M.D., looked at the association of neighborhood disadvantage and the biology of aggressive non-small cell lung cancer. Non-small cell lung cancer has a disproportionately higher incidence and mortality rate in marginalized communities, who often reside in neighborhoods with adverse conditions influenced by economic, housing, education, transportation and environmental factors. Researchers looked at 426 non-small cell lung cancer patients treated at City of Hope and found that those who lived in disadvantaged neighborhoods were more likely to have a somatic KRAS mutation — a mutation that is associated with lower survival. This relationship was consistent even when smoking status and pollution were considered and suggests neighborhood disadvantage may be an important determinate of aggressive non-small cell lung cancer biology, possibly explaining why marginalized individuals have worse outcomes.

Predictors of clonal immune responses in colorectal cancer
Time: April 10 from 8:30 a.m. to 11:59 a.m. EDT
Stephen Gruber, M.D., Ph.D., M.P.H., director of City of Hope’s Center for Precision Medicine, studied clinical and epidemiologic predictors of clonal immune responses in colorectal cancer to better understand what causes diverse immune responses. He and his colleagues found that the use of statins and daily aspirin for more than five years prior to when a patient was diagnosed with colon cancer was strongly associated with the quality and behavior of the immune cells (T cells) within the tumor itself. Their research suggests that adaptive immune response may be linked to modifiable factors. Having a better understanding of the mechanisms that regulate immune responses in colorectal cancer may have implications for chemoprevention and immunotherapy.

Novocure Announces 26 Presentations at American Association for Cancer Research (AACR) Annual Meeting 2021 Suggesting Broad Applicability of Tumor Treating Fields

On April 9, 2021 Novocure (NASDAQ: NVCR) reported 26 presentations on Tumor Treating Fields suggesting broad applicability of Tumor Treating Fields at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021, held virtually from April 10 to April 15, 2021 (Press release, NovoCure, APR 9, 2021, View Source [SID1234577801]). Research spanning seven solid tumor types confirms the anti-mitotic effect of Tumor Treating Fields and further explores downstream effects to identify optimal use of Tumor Treating Fields, including the role of Tumor Treating Fields-induced immunogenic cell death.

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Presentation highlights include research showing the induction of robust anti-tumor immunity by Tumor Treating Fields in glioblastoma, the immunoregulatory role of Tumor Treating Fields on macrophage polarization, the effects of Tumor Treating Fields on DNA damage repair, and replication stress as a pathway to illuminate novel combination therapy options.

"Ongoing research at Novocure and throughout the global scientific community continues to build upon and deepen our understanding of Tumor Treating Fields as we strive to extend survival in some of the most aggressive forms of cancer," said Dr. Uri Weinberg, Novocure’s Chief Science Officer. "We are honored to be a part of the invaluable exchange of scientific information at the AACR (Free AACR Whitepaper) Annual Meeting and are particularly pleased to see an increasing focus on the effect of Tumor Treating Fields on the immune system’s response against cancer."

Presentations from Novocure-sponsored and partner programs include:

(Poster #: CT258) EF-32 (TRIDENT): A pivotal randomized trial of radiation therapy concomitant with temozolomide +/- Tumor Treating Fields (TTFields) in newly diagnosed glioblastoma. W. Shi (Clinical Trials)

(Poster #: LB064) Long-term application of TTFields in anaplastic astrocytoma – a case study. D. Markovic (Clinical Research)

(Poster #: 2635) Contemporary clinical practice guidelines for the management of glioblastoma: an international survey. A. Lawson McLean (Science and Health Policy)

(Poster #: 1065) Concomitant dexamethasone treatment and tumor treating fields induced cell death in glioblastoma. B. Linder (Combination Therapies)

(Poster #: 2634) French health utilities for patients with glioblastoma using TTFields. G. Chavez (Science and Health Policy)

(Poster #: 717) Rapid transformation of TTFields care-delivery during COVID-19 pandemic to optimize treatment of patients with glioblastoma (GBM). P. Frongillo (COVID-19 and Cancer)

(Poster #: 1435) The distribution of Tumor Treating Fields is effected by cell confluence and pores in the membrane. T. Marciano (Experimental and Molecular Therapeutics)

(Poster #: 3070) Lung cancer TTFields treatment planning sensitivity to errors in torso segmentation. H. Ben Atya (Tumor Biology)

(Poster #: 3071) A method for infratentorial structures segmentation for tumor treating fields treatment planning. Y. Glozman (Tumor Biology)

(Poster #: 1692) A novel immunoregulatory role of Tumor Treating Fields (TTFields) on macrophage polarization. B. Brant (Immunotherapy, Preclinical and Clinical)

(Poster #: 1063) Effectiveness of Tumor Treating Fields (TTFields) in combination with sorafenib for treatment of hepatocellular carcinoma in vitro and in vivo. A. S. Davidi (Experimental and Molecular Therapeutics)

(Poster #: 1317) Inovivo: a dedicated system for delivery of therapeutic level Tumor Treating Fields (TTFields) to mice. S. Davidi (Experimental and Molecular Therapeutics)

(Poster #: 1382) Targeting Akt signaling pathway potentiates the antitumor effect of Tumor Treating Fields (TTFields) in vitro. A. Klein-Goldberg (Experimental and Molecular Therapeutics)

(Poster #: 1186) Efficacy of Tumor Treating Fields (TTFields) in mesothelioma is associated with reduced capacity for DNA damage repair. H. Mumblat (Experimental and Molecular Therapeutics)

(Poster #: 279) Transient opening of the blood brain barrier by Tumor Treating Fields (TTFields). C. Tempel Brami (Cancer Chemistry)

(Poster #: 1064) Antiproliferative effects of Tumor Treating Fields (TTFields) in human mesothelioma cell lines. M. Lupi (Combination Therapies)

(Poster #: 1200) Long-duration term TTFields treatment of glioblastoma cells induces cell death. S. Castiglione (New Targets)

(Poster #: 1037) Valproic acid (VPA) combined with Tumor Treating Fields (TTFields) in vitro decreases cellular proliferation and increases clonogenic potential of glioblastoma (GBM) cells. S. Michelhaugh (Combination Therapies)

(Poster #: 1007) Patient-derived metastatic renal carcinoma cells are highly sensitive to Tumor Treating Fields (TTFields) in vitro. S. Michelhaugh (Cellular Responses to Anticancer Drugs)

(Poster #: 2011) Tumor Treating Fields Induce Cellular and Morphologic Changes that Include Disruption of Intercellular Communication Networks in Malignant Pleural Mesothelioma. A. Sarkari (Cell-cell Interactions)

(Poster #: 1678) Induction of Robust Anti-Tumor Immunity by Tumor Treating Fields in Glioblastoma. D. Chen (Immune Response to Therapies)

(Poster #: 3063) Prostaglandin e receptor 3 mediates resistance to Tumor Treating Fields in glioblastoma cells. D. Chen (Radiation Science)

(Poster #: 1051) Targeting replication stress pathway provides an avenue for novel combination therapy options including TTFields plus chemo agents which increase replication stress. N. Karanam (Combination Therapies)

(Poster #: 1975) Tumor Treating Fields Triggers Autophagy Pathway Activation at Primary Cilia to Promote Glioma Cell Survival. P. Shi (Cell Signaling)

(Poster #: 3049) Tumor treating fields induce DNA damage and apoptosis in medulloblastoma. R. Nitta (Pediatric Cancer: Basic Science)

(Poster #: LB023) Drug loaded nanoparticle targeting of pancreatic cancer using tumor treating fields (TTFields). P. Desai (Cancer Chemistry)

About Tumor Treating Fields
Tumor Treating Fields, or TTFields, are electric fields that disrupt cancer cell division.

When cancer develops, rapid and uncontrolled division of unhealthy cells occurs. Electrically charged proteins within the cell are critical for cell division, making the rapidly dividing cancer cells vulnerable to electrical interference. All cells are surrounded by a bilipid membrane, which separates the interior of the cell, or cytoplasm, from the space around it. This membrane prevents low frequency electric fields from entering the cell. TTFields, however, have a unique frequency range, between 100 to 500 kHz, enabling the electric fields to penetrate the cancer cell membrane. As healthy cells differ from cancer cells in their division rate, geometry and electric properties, the frequency of TTFields can be tuned to specifically affect the cancer cells while leaving healthy cells mostly unaffected.

Whether cells are healthy or cancerous, cell division, or mitosis, is the same. When mitosis starts, charged proteins within the cell, or microtubules, form the mitotic spindle. The spindle is built on electric interaction between its building blocks. During division, the mitotic spindle segregates the chromosomes, pulling them in opposite directions. As the daughter cells begin to form, electrically polarized molecules migrate towards the midline to make up the mitotic cleavage furrow. The furrow contracts and the two daughter cells separate. TTFields can interfere with these conditions. When TTFields are present in a dividing cancer cell, they cause the electrically charged proteins to align with the directional forces applied by the field, thus preventing the mitotic spindle from forming. Electrical forces also interrupt the migration of key proteins to the cell midline, disrupting the formation of the mitotic cleavage furrow. Interfering with these key processes disrupts mitosis and can lead to cell death.

TTFields is intended principally for use together with other standard-of-care cancer treatments. There is a growing body of evidence that supports TTFields’ broad applicability with certain other cancer therapies, including radiation therapy, certain chemotherapies and certain immunotherapies. In clinical research and commercial experience to date, TTFields has exhibited no systemic toxicity, with mild to moderate skin irritation being the most common side effect.

Fundamental scientific research extends across two decades and, in all preclinical research to date, TTFields has demonstrated a consistent anti-mitotic effect. The TTFields global development program includes a broad range of clinical trials across all phases, included four phase 3 pivotal trials in a variety of tumor types. To date, more than 18,000 patients have been treated with TTFields.

MiNA Therapeutics Presents Translational Data at AACR Supporting MTL-CEBPA as Immunological Cancer Combination Treatment

On April 9, 2021 MiNA Therapeutics, the pioneer in RNA activation (RNAa) therapeutics, reported translational data supporting the favourable immunological effects of MTL-CEBPA and its benefits in combination with other cancer therapies including anti-PD1 checkpoint inhibition (Press release, MiNA Therapeutics, APR 9, 2021, View Source [SID1234577800]). The studies combine pre-clinical research conducted at the Wistar Institute as well as biomarker analysis of the previously completed OUTREACH clinical trial. MTL-CEBPA is the first candidate from MiNA’s pipeline of small activating RNA therapeutics, a new class of medicines to restore normal cell function. The data will be presented during a poster session at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, held virtually from April 10 – April 15, 2021.

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"These new translational findings confirm the important role of MTL-CEBPA in cancer immunology," said Robert Habib, CEO of MiNA Therapeutics. "We continue to deepen our understanding of the immunological effects of MTL-CEBPA for the treatment of patients with advanced cancer and other indications and will analyse its effects as part of our ongoing clinical studies. Collectively, the data further demonstrate how RNA activation can access a previously undruggable target for patient benefit."

In pre-clinical studies, MTL-CEBPA was shown to counteract a key cancer immune evasion pathway by inhibiting immune suppression by myeloid cells. MTL-CEBPA was also shown to potentiate the anti-tumour activity of immunotherapies including anti-PD1 in models of lung and colon cancer. In addition, samples were analysed from advanced liver cancer patients treated with MTL-CEBPA as part of the OUTREACH clinical trial. Analysis of mRNA, protein and cellular biomarkers in peripheral blood confirmed that MTL-CEBPA reduced markers associated with immunosuppressive myeloid cells. Analysis of cellular biomarkers in tumour biopsies showed that those patients who responded to MTL-CEBPA combination therapy had high tumour infiltrations of immunosuppressive macrophages prior to treatment, which were depleted with treatment.

The results validate and expand on previously presented pre-clinical research findings on MTL-CEBPA as an immunological combination treatment in liver cancer and colon cancer. MTL-CEBPA demonstrated signals of activity in a Phase 1b trial in advanced liver cancer, including durable and complete tumour responses as a combination treatment with a standard of care tyrosine kinase inhibitor. A Phase 2 study in advanced liver cancer is expected to commence later this year. MTL-CEBPA is currently being evaluated in a second study in patients with advanced solid tumours in the TIMEPOINT Phase 1/1b clinical trial in combination with a leading checkpoint inhibitor.

The poster will be made available on the Company’s website in the Publications section under "RNA Activation" at the start of the conference on April 10th, 2021.

Presentation information

Title: Up-regulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and cancer patients
Abstract No: 1730
Session: Immunology – Immunomodulatory Agents and Interventions
Presenter: Mikael Sodergren

About MTL-CEBPA
MTL-CEBPA is the first therapy that specifically up-regulates CCAAT/enhancer binding protein alpha (C/EBP-α), a transcription factor that acts as a master regulator of myeloid cell lineage determination and differentiation. Dysregulated myeloid cells have been implicated in several diseases and in solid tumour cancers have been identified as a critical barrier for many therapies to induce clinical responses. In pre-clinical studies MTL‑CEBPA has been shown to improve the anti-tumour activity of cancer therapies by targeting dysregulated myeloid cells and reducing their suppressive effect in the tumour micro-environment. MTL-CEBPA is currently in clinical development as a combination therapy for the treatment of advanced liver cancer and advanced solid tumour malignancies.

Aptevo Therapeutics to Present at the American Association for Cancer Research Virtual Annual Meeting

On April 9, 2021 Aptevo Therapeutics Inc. (NASDAQ:APVO), a clinical-stage biotechnology company focused on developing novel immuno-oncology therapeutics based on its proprietary ADAPTIRTM and ADAPTIR-FLEXTM platform technologies, reported that it will present two new posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting, to be held in two virtual sessions – Saturday, April 10th to Thursday, April 15th, 2021 and Monday, May 17th to Friday, May 21st, 2021 (Press release, Aptevo Therapeutics, APR 9, 2021, View Source [SID1234577799]).

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The posters will provide preclinical updates on APVO603 and Aptevo’s newest pipeline candidate, APVO442.

Title: APVO603: A Dual 4-1BB and OX40 bispecific approach utilizing ADAPTIR technology designed to deliver a conditional T cell/NK response against solid tumors (LB173)

Summary: The data to be presented will highlight the potential benefits of dual targeting of 4-1BB and OX40 by APVO603. In vitro data includes demonstration of APVO603’s ability to reduce or reverse the negative effects of T-cell exhaustion and suppressive immune responses by augmenting cytokine production and reducing markers of T-cell exhaustion following repeat stimulation. In preclinical in vivo studies, APVO603 therapy induced a dose-dependent anti-tumor response and significantly increased the survival of mice in a murine bladder cancer model. A non-GLP NHP PK/Tox study was completed and it was found that APVO603 had a favorable safety profile without liver toxicity and a PK profile that supports clinical dosing. CMC activities are in progress and IND-enabling studies are underway to progress the program towards clinical development.

Title: APVO442: A bispecific T cell-engaging candidate utilizing the ADAPTIR-FLEX platform technology with unique properties designed to optimize drug tumor distribution and cytotoxic response against PSMA-expressing solid tumors

Summary: The data to be presented will highlight the unique properties of APVO442, Aptevo’s first molecule utilizing our ADAPTIR-FLEX technology, designed with low affinity, monovalent targeting of CD3 and high affinity, bivalent targeting of PSMA to potentially reduce safety signals and improve efficacy for treatment of a solid tumor. In vitro, APVO442 retains strong binding to tumor cell lines with a range of (high to low) surface PSMA expression, and demonstrates reduced binding to CD3+ T cell lines when compared to higher affinity CD3 binding molecules. In vitro efficacy studies show that, despite lower CD3 binding affinity, APVO442 elicits equivalent T-cell activation, proliferation, and cytotoxicity against PSMA+ tumor cells, while limiting cytokine release, when compared to higher affinity CD3 engaging molecules. In vivo, APVO442 demonstrated a dose-dependent ability to limit tumor burden at responses comparable to a high affinity T-cell engager response in a murine xenograft PSMA+ prostate cancer model. APV0442 retains key manufacturability characteristics of the ADAPTIR platform and preclinical data to support the potential for a beneficial safety and efficacy profile. Continued pre-clinical evaluation and CMC efforts are ongoing to progress APVO442 toward clinical development.

Details of the e-Poster Presentations: The abstracts and the accompanying e-posters will be available in the Virtual Poster Hall to registered attendees from 8:30 am EST on Saturday, April 10th, 2021, until the Virtual Poster Hall closes on Monday June 21st, 2021. Chat and live meeting requests will be available for questions and discussion with the presenters. Details can be found on the AACR (Free AACR Whitepaper) abstract website and will also be posted on the Aptevo Therapeutics website.

Turning Point Therapeutics Announces New Preclinical Data for Three Drug Candidates

On April 9, 2021 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported new preclinical data supporting the ongoing development of three of its drug candidates, repotrectinib, TPX-0022 and TPX-0131 (Press release, Turning Point Therapeutics, APR 9, 2021, View Source [SID1234577798]). The findings will be presented this weekend at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, which is convening virtually through April 14.

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For lead drug candidate, repotrectinib, poster presentations will highlight new preclinical combination data with MEK and MEK/Raf inhibitors, as well as repotrectinib’s potency against wildtype and mutant TRKA/B/C as compared to approved TRK inhibitors. The preclinical studies found that repotrectinib combinations with approved MEK inhibitor, trametinib, or investigational MEK/Raf inhibitor, VS-6766, were more effective than single-agent treatment in patient-derived KRAS mutant G12D/V lung and G12D/V/R pancreatic cancer models. Based on the findings and additional preclinical support presented previously, Turning Point anticipates the first cohort of its planned Phase 1/2 TRIDENT-2 study will examine the safety, tolerability, pharmacokinetics, and any early signals of efficacy of repotrectinib in combination with trametinib in patients with KRAS mutant G12D advanced solid tumors.

"We are encouraged by the new preclinical data our research team has generated in support of our ongoing development of repotrectinib, TPX-0022 and TPX-0131," said Athena Countouriotis, M.D., president and CEO. "In particular, our preclinical models continue to suggest that the combination of repotrectinib with MEK inhibitors can suppress mutant KRAS signaling to achieve more potent and durable anti-tumor activity. We look forward to studying this further in the first cohort of our planned TRIDENT-2 combination study.

"In addition, preclinical studies show repotrectinib is highly potent against wild type TRK fusions and is less affected by NTRK resistance mutations than approved therapies, with strong potency in both in vitro and in vivo studies. We look forward to sharing additional clinical data from our TRIDENT-1 study of repotrectinib in the second half of the year."

TPX-0022, MET, SRC, CSF1R Inhibitor
For MET/SRC/CSF1R inhibitor TPX-0022, the company will present preclinical data demonstrating potential utility in combination with immune checkpoint inhibitors. In a syngeneic xenograft tumor model, TPX-0022 treatment downregulated immunosuppressive cytokines, increased anti-tumor M1 macrophages, and enriched levels of CD8+ cytotoxic T cells. TPX-0022 had single agent in vivo efficacy and enhanced the efficacy of an anti-PD-1 inhibitor. With the new data, Turning Point is evaluating a potential additional combination study of TPX-0022 and an anti-PD-1 checkpoint inhibitor. In the second half of 2021, the company plans to provide a clinical data update from the Phase 1 dose finding portion of its ongoing SHIELD-1 study and initiate its planned Phase 1b/2 SHIELD-2 clinical study of TPX-0022 in combination with an EGFR targeted therapy.

TPX-0131, ALK Inhibitor
For its ALK-inhibitor, TPX-0131, Turning Point will present preclinical data showing its potential to cross the blood-brain barrier and its potency against wild type ALK and a broad spectrum of acquired ALK resistance mutations, including the G1202R solvent front mutation, L1196M gatekeeper mutation, and the G1202R/L1196M and /L1198F compound mutations. Turning Point plans to initiate a Phase 1/2 study in patients with ALK-positive TKI-pretreated advanced non-small cell lung cancer in the second quarter of 2021.

AACR plans to make poster presentations available via its website on Saturday, April 10. The four posters to be presented are:

Title: Repotrectinib increases effectiveness of MEK inhibitors in KRAS mutant cancer models
Abstract Number: 1104

Title: Molecular characteristics of repotrectinib that enable potent inhibition of TRK fusion proteins and broad mutant selectivity
Abstract Number: 1119

Title: TPX-0022, a potent MET/SRC/CSF1R inhibitor that modulates the tumor immune microenvironment in preclinical models
Abstract Number: 1444

Title: TPX-0131, a potent inhibitor of wild type ALK and a broad spectrum of both single and compound ALK resistance mutations
Abstract Number: 1469