Multi-omic Molecular Profiling Research Articles

Molecular and physiological changes in the SpaceX Inspiration4 civilian crew.

Human spaceflight has historically been managed by government agencies, such asin the NASA Twins Study1, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX Inspiration4 mission launched the first all-civilian crew to low Earth orbit, which included the youngest American astronaut (aged 29), new in-flight experimental technologies (handheld ultrasound imaging, smartwatch wearables and immune profiling), ocular alignment measurements and new protocols for in-depth, multi-omic molecular and cellular profiling. Here we report the primary findings from the 3-day spaceflight mission, which induced a broad range of physiological and stress responses, neurovestibular changes indexed by ocular misalignment, and altered neurocognitive functioning, some of which match those oflong-term spaceflight2, but almost all of which did not differ from baseline (pre-flight) after return to Earth. Overall, these preliminary civilian spaceflight data suggest that short-duration missions do not pose a significant health risk, and moreover present a rich opportunity to measure the earliest phases of adaptation to spaceflight in the human body at anatomical, cellular, physiological and cognitive levels. Finally, these methods and results lay the foundation for an open, rapidly expanding biomedical database for astronauts3, which can inform countermeasure development for both private and government-sponsored space missions.

Multi‐omic molecular profiling guide’s efficacious treatment selection in refractory metastatic breast cancer: a prospective phase II clinical trial

This prospective phase II clinical trial (Side Out 2) explored the clinical benefits of treatment selection informed by multi‐omic molecular profiling (MoMP) in refractory metastatic breast cancers (MBCs). Core needle biopsies were collected from 32 patients with MBC at trial enrollment. Patients had received an average of 3.94 previous lines of treatment in the metastatic setting before enrollment in this study. Samples underwent MoMP, including exome sequencing, RNA sequencing (RNA‐Seq), immunohistochemistry, and quantitative protein pathway activation mapping by Reverse Phase Protein Microarray (RPPA). Clinical benefit was assessed using the previously published growth modulation index (GMI) under the hypothesis that MoMP‐selected therapy would warrant further investigation for GMI ≥ 1.3 in ≥ 35% of the patients. Of the 32 patients enrolled, 29 received treatment based on their MoMP and 25 met the follow‐up criteria established by the trial protocol. Molecular information was delivered to the tumor board in a median time frame of 14 days (11–22 days), and targetable alterations for commercially available agents were found in 23/25 patients (92%). Of the 25 patients, 14 (56%) reached GMI ≥ 1.3. A high level of DNA topoisomerase I (TOPO1) led to the selection of irinotecan‐based treatments in 48% (12/25) of the patients. A pooled analysis suggested clinical benefit in patients with high TOPO1 expression receiving irinotecan‐based regimens (GMI ≥ 1.3 in 66.7% of cases). These results confirmed previous observations that MoMP increases the frequency of identifiable actionable alterations (92% of patients). The MoMP proposed allows the identification of biomarkers that are frequently expressed in MBCs and the evaluation of their role as predictors of response to commercially available agents. Lastly, this study confirmed the role of MoMP for informing treatment selection in refractory MBC patients: more than half of the enrolled patients reached a GMI ≥ 1.3 even after multiple lines of previous therapies for metastatic disease.

Multi-omic molecular profiling reveals potentially targetable abnormalities shared across multiple histologies of brain metastasis.

The deadly complication of brain metastasis (BM) is largely confined to a relatively narrow cross-section of systemic malignancies, suggesting a fundamental role for biological mechanisms shared across commonly brain metastatic tumor types. To identify and characterize such mechanisms, we performed genomic, transcriptional, and proteomic profiling using whole-exome sequencing, mRNA-seq, and reverse-phase protein array analysis in a cohort of the lung, breast, and renal cell carcinomas consisting of BM and patient-matched primary or extracranial metastatic tissues. While no specific genomic alterations were associated with BM, correlations with impaired cellular immunity, upregulated oxidative phosphorylation (OXPHOS), and canonical oncogenic signaling pathways including phosphoinositide 3-kinase (PI3K) signaling, were apparent across multiple tumor histologies. Multiplexed immunofluorescence analysis confirmed significant T cell depletion in BM, indicative of a fundamentally altered immune microenvironment. Moreover, functional studies using in vitro and in vivo modeling demonstrated heightened oxidative metabolism in BM along with sensitivity to OXPHOS inhibition in murine BM models and brain metastatic derivatives relative to isogenic parentals. These findings demonstrate that pathophysiological rewiring of oncogenic signaling, cellular metabolism, and immune microenvironment broadly characterizes BM. Further clarification of this biology will likely reveal promising targets for therapeutic development against BM arising from a broad variety of systemic cancers.

Phase II trial of BPM31510-IV plus gemcitabine in advanced pancreatic ductal adenocarcinomas (PDAC).

723 Background: BPM31510-IV is an Ubidecarenone (CoQ10) drug-lipid conjugate nanodispersion targeting metabolic machinery in cancer, shifting bioenergetics from lactate dependency towards mitochondrial OxPhos to generate ROS and activate apoptosis. An MTD of BPM31510-IV in combination with gemcitabine was established at 110mg/kg in a Phase I clinical trial, which determined the dose for the Phase 2 investigation. Methods: Eligible patients (aged ≥ 18 y) with relapsed/refractory PDAC to standard treatment (ST) and met inclusion/exclusion criteria were recruited. Patients received 110mg/kg IV BPM31510 in combination with gemcitabine in a 144-hour infusion. Tumor response was evaluated at week 10 and then every 8 weeks. Study endpoints assessed were Overall Response Rate (ORR), Overall Survival (OS), Progression-Free Survival (PFS), Time to Progression (TTP), Tumor Response using Adaptive Molecular Responses (multi-omic molecular profiling), changes in CA 19-9 levels and patient reported Quality of Life (QOL) using the validated FACT-HEP PRO. A comprehensive multi-omic profiling for identification of biomarkers for patient stratification was explored. Results: Of the 35 patients enrolled to receive therapy, 18 patients met criteria of an adequately treated cohort (ATC- received BPM31510-IV + gemcitabine for 30 days over 2 cycles and had a RECIST 1.1 evaluation) while remaining (n = 17) had progressive disease (PD). Half of the ATC population (n = 9/18, 50%) achieved best ORR of stable disease (SD); 10/18 (55 %) demonstrated SD as best response at target lesions and 8/18 demonstrated SD at end of Cycle 2. The mTTP was 121 days (70 – 147, 95% CI); PFS 118 days (70 – 131, 95% CI) and OS 218 days (131 – 228, 95% CI), respectively. Overall, BPM31510-IV was well tolerated; the most common AE’s were GI related. Conclusions: The efficacy signal observed in this heavily pretreated population in addition to the toxicity profile warrants further clinical investigation of BPM31510-IV + gemcitabine in advanced PDAC. Clinical trial information: NCT02650804 . [Table: see text]

Multi-omic based molecular profiling of advanced cancer identifies treatable targets and improves survival in individual patients.

A proof-of-concept study was conducted to assess whether patients with advanced stage IV cancer for whom predominantly no standard therapy was available could benefit from comprehensive molecular profiling of their tumor tissue to provide targeted therapy. Tumor samples of 83 patients were collected under highly standardized conditions and analyzed using immunohistochemistry, next-generation sequencing and phosphoprotein profiling. Expression and phosphorylation of key oncogenic pathways were measured to identify targets at the (phospho-) proteomic level. At genomic level, 50 oncogenes and tumor suppressor genes were analyzed. Based on molecular profiling, targeted therapies were decided by the attending oncologist. Accordingly, 28 patients who met the defined criteria fell in two equal-sized groups. One group received targeted therapies while the other did not. Following six months of treatment, disease control was achieved by 49% of patients receiving targeted therapy (complete remission, 14%; partial remission, 21%; stable disease, 14%; disease progression, 36%; death, 14%) and 21% of patients receiving non-targeted therapy (stable disease, 21%; disease progression, 64%; death, 14%). Individual patients experienced dramatic responses to a therapy which otherwise would not have been applied. This approach clarifies the value of multi-omic molecular profiling for cancer diagnostics.

P2.15-13 Implementation of a Democratized Approach to Multi-Omic Molecular Profiling Via the LungMATCH Program.

For metastatic non-small cell lung cancer (NSCLC) guidelines include molecular testing for actionable biomarkers and recommend broad profile testing. Previous studies indicate that many patients with NSCLC are not receiving testing, even for actionable changes in EGFR, ALK, and ROS, BRAF, and PD-L1. There are widespread gaps in the community setting and Lung Cancer Alliance data shows that less than 50% of callers to the patient HelpLine have had molecular testing on their lung cancer. The LungMATCH molecular testing program is operationalized via a turn-key precision medicine (PM) operation system. This approach provides a standardized workflow from tissue acquisition through multi-omic molecular profiling, treatment history integration, and AI-based computational analysis to produce a treatment decision support tool of therapeutic options matched to the patient. Longitudinal outcome is collected on every patient along with treatment decisions and patient experience. The majority of the patient referrals (72%) came from non-academic centers across a wide geographic region that covered nearly 75% of the United States (36/50 states). Barriers to signing informed consent and completing biopsy have been identified including: patients in poor health, cost concerns, unsupportive physicians, and patient loyalty to the physician (discomfort with advocating for testing). For patients who have received reports, 72% (12/17) had actionable genomic alterations that indicated either a standard of care agent or a clinical trial. An additional 82% (9/11) had actionable proteomic findings and 31% (5/16) had high tumor mutational burden. There is broad patient interest in accessing PM information but still many barriers to widespread adoption. The LungMATCH program provides a turn-key solution to help provide a facile means to “democratize” access to PM information unbound by geography or community/academic setting. Importantly, the majority of patients who received a completed profiling report had actionable molecular alterations, which underscores the potential impact of testing. Treatment decisions and patient outcomes continue to be followed.

417PD - Combination therapy optimization in gastrointestinal cancers using multi-omic molecular profiling

417PD - Combination therapy optimization in gastrointestinal cancers using multi-omic molecular profiling

Abstract B26: Addressing gaps in molecular testing for patients with lung cancer

Abstract Background: For metastatic non-small cell lung cancer (NSCLC), guidelines include molecular testing for actionable biomarkers and recommend broad profile testing. Despite these recommendations, previous studies indicate that not all patients with NSCLC are receiving testing, even for actionable mutations in EGFR, ALK, and ROS. There are widespread gaps in the community setting, and Lung Cancer Alliance (LCA) data show that fewer than 50% of callers to the patient HelpLine have had molecular testing on their lung cancer. Methods: To help address this problem, we developed an innovative program that combines direct patient services with increasing enrollment to clinical studies. Patients are recruited to the LungMATCH molecular testing program through conversations on the LCA HelpLine. They are then entered into the Perthera Program to receive a Perthera Report (PR) through consent into an IRB-approved registry protocol. The Program includes tissue acquisition, multi-omic molecular profiling, and collection of patient treatment history followed by integration into a computational pipeline with extensive drug and clinical trial databases to provide ranked therapeutic options matched to the patient. An every-patient, real-time medical review board then reviews and approves the PR. PRs are returned to both treating physicians and patients. Data are being collected longitudinally on treatment decisions, patient outcomes including progression-free and overall survival, and patient experience. Results: In the first nine months, 72 patients were referred into the Program. The majority of the patients (76%) came from community centers across a wide geographic region in the United States. There were a number of barriers to signing informed consent and completing biopsy identified. Most common reasons included patients in poor health, cost concerns, unsupportive doctors, and patient loyalty to the physician (discomfort with advocating for the testing). Of the first 11 patients who received a PR, 9 had actionable alterations that indicated either a standard-of-care agent or a clinical trial. Actionable alterations were identified by next-generation sequencing, in situ hybridization, and immunohistochemistry. Two patients also had high tumor mutation burden. Conclusions: We introduced a nonprofit-corporate partnership that navigates patients and their physicians through a comprehensive precision-therapy program. We have demonstrated that this type of program is feasible and there is broad patient interest, particularly from patients seen in nonacademic settings. A number of barriers were identified and are being addressed. Importantly, the majority of patients who received a completed PR (82%) had actionable molecular alterations, underscoring the potential impact of the program. Citation Format: Jennifer C. King, Andrew Ciupek, Tara Perloff, Ashley Blanchard, Kimberly Mason, Edik Blais, David Halverson, Joseph Bender, Subha Madhavan, Emanuel Petricoin. Addressing gaps in molecular testing for patients with lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B26.

Multi-omic molecular profiling of lung cancer in COPD.

Chronic obstructive pulmonary disease (COPD) is a known risk factor for developing lung cancer but the underlying mechanisms remain unknown. We hypothesise that the COPD stroma contains molecular mechanisms supporting tumourigenesis.We conducted an unbiased multi-omic analysis to identify gene expression patterns that distinguish COPD stroma in patients with or without lung cancer. We obtained lung tissue from patients with COPD and lung cancer (tumour and adjacent non-malignant tissue) and those with COPD without lung cancer for profiling of proteomic and mRNA (both cytoplasmic and polyribosomal). We used the Joint and Individual Variation Explained (JIVE) method to integrate and analyse across the three datasets.JIVE identified eight latent patterns that robustly distinguished and separated the three groups of tissue samples (tumour, adjacent and control). Predictive variables that associated with the tumour, compared to adjacent stroma, were mainly represented in the transcriptomic data, whereas predictive variables associated with adjacent tissue, compared to controls, were represented at the translatomic level. Pathway analysis revealed extracellular matrix and phosphatidylinositol-4,5-bisphosphate 3-kinase-protein kinase B signalling pathways as important signals in the tumour adjacent stroma.The multi-omic approach distinguishes tumour adjacent stroma in lung cancer and reveals two stromal expression patterns associated with cancer.

Implementation of a democratized approach to multi-omic molecular profiling via the LungMATCH program.

e21033Background: For metastatic non-small cell lung cancer (NSCLC) guidelines include molecular testing for actionable biomarkers and recommend broad profile testing. Previous studies indicate tha...

P1.01-036 Identifying and Addressing Gaps in Molecular Testing for Patients with Lung Cancer

For metastatic non-small cell lung cancer (NSCLC), guidelines include molecular testing for actionable biomarkers and recommend broad profile testing. Yet previous studies indicate that not all patients with NSCLC are receiving testing, even for actionable mutations in EGFR, ALK, and ROS. We hypothesized that rates of molecular testing would be low for patients calling a community HelpLine and that we could potentially increase testing rates with one-on-one caller education and providing free precision medicine services. Caller statistics were collected on the toll-free Lung Cancer Alliance (LCA) HelpLine from Sept 1, 2016 – May 31, 2017. Recruitment to the LungMATCH molecular testing program began Nov 10, 2017. Patients are recruited through conversations on the LCA HelpLine, and then entered into Perthera Cancer Analysis (PCA) through consent into an IRB-approved registry protocol. PCA includes tissue acquisition, multi-omic molecular profiling, and medical review of testing results and clinical and treatment history. PCA reports are returned to both treating physicians and patients. Data is being collected longitudinally on treatment decisions, patient outcomes including progression-free and overall survival, and patient experience. Data from the LCA Helpline identified a gap in molecular testing. 44% (100/228) of patients who were asked if they received any kind of molecular testing replied “No”. Of 46 patients who were tested and knew the results, patients indicated changes in EGFR (25), PD-L1 (10), ALK (5), KRAS (4), MET(2), BRAF, and RET. Most of these alterations are potentially actionable. From Nov 10, 2016 – May 31, 2016, 63 interested patients were referred for PCA. Sixteen patients consented and eight more are currently in the consent process. Reasons for non-consent include: doctor refusal, initiation of testing at the treating institution, concern about financial implications, and seven deaths. Ten patients are actively undergoing PCA and six have received completed PCA reports. Of those six, three patients reported that treatment decisions were made using the molecular testing information. Updated results will be presented. Caller data indicate that patients with lung cancer are not receiving molecular testing in accordance to guidelines. To address this problem, we introduced a program through a nonprofit-corporate partnership that navigates patients and their physicians through a comprehensive precision therapy program. This type of program is feasible and there is patient interest.

472TiP - Phase 2 clinical investigation of BPM31510 (ubidecarenone) alone and in combination with gemcitabine in patients with advanced pancreatic cancer

Background: BPM31510 is an ubidecarenone lipid nanodispersion that switches cancer energy generation from glycolysis to mitochondrial oxidative phosphorylation to elicit anticancer effect. BPM31510 is well tolerated as a monotherapy and at an established MTD of 110mg/kg in combination with Gemcitabine in a Phase I clinical trial. Preclinical in vivo pancreatic models demonstrate that BPM31510 alone and in combination with gemcitabine significantly improves duration of survival; supporting the Phase 2 evaluation of BPM31510 in patients with advanced metastatic adenocarcinoma. Trial design: Eligible patients (aged ≥ 18 y) relapsed/refractory to standard treatment (ST) and met inclusion/exclusion criteria. Each patient receives 110mg/kg IV BPM31510 in a 144-hour infusion alone or in combination with gemcitabine. Tumor response is evaluated at wk10 and then every 8 wks. Investigator observations and reports by treated patients provide clinical assessments not specifically defined in the protocol. This study initially will enroll ten (10) patients in the BPM31510 (monotherapy arm) and ten (10) patients in the BPM31510 plus gemcitabine (combination therapy arm) with intent to enroll the additional 15 patients into the applicable treatment arm(s) into the expansion stage based on RECIST v1.1 clinical response. The goal is to evaluate the Overall Response Rate (ORR) in patients treated with BPM31510 alone or in combination with gemcitabine along with Overall Survival (OS); Progression-Free Survival (PFS); Time to Progression (TTP); Tumor Response using Adaptive Molecular Responses (multi-omic molecular profiling); Evaluate Change in CA 19-9 levels and patient reported Quality of Life using the validated FACT-HEP patient-reported outcomes instrument. Clinical trial identification: BPM31510IV-05 Legal entity responsible for the study: BERG, LLC Funding: BERG, LLC Disclosure: A. Niewiarowska: Clinical investigator paid by BERG, LLC to conduct studies. R. Sarangarajan: Employee, co-founder and has stock options of BERG, LLC. D. Lucius: Employee and has stock options of BERG, LLC. N. Narain: Employee, co-founder and has stock options of BERG, LLC R.K. Raminathan: Clinical investigator paid by BERG, LLC to conduct studies. M. Hidalgo: Clinical investigator paid by BERG, LLC to conduct studies.

Enrichment of PI3K-AKT-mTOR Pathway Activation in Hepatic Metastases from Breast Cancer.

Purpose: Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K-AKT-mTOR pathway is associated with specific sites of breast cancer metastasis.Experimental Design: Next-generation sequencing-based whole-exome sequencing was coupled with reverse-phase protein microarray (RPPA) functional signaling network analysis to explore the PI3K-AKT-mTOR axis in 32 pretreated breast cancer metastases. RPPA-based signaling data were further validated in an independent cohort of 154 metastatic lesions from breast cancer and 101 unmatched primary breast tumors. The proportion of cases with PI3K-AKT-mTOR genomic alterations or signaling network activation were compared between hepatic and nonhepatic lesions.Results:PIK3CA mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than nonhepatic lesions (P < 0.01, P = 0.056, and P = 0.053, respectively). However, PIK3CA mutations alone were insufficient in predicting protein activation (P = 0.32 and P = 0.19 for activated AKT and p70S6K, respectively). RPPA analysis of an independent cohort of 154 tumors confirmed the relationship between pathway activation and hepatic metastasis [AKT (S473), mTOR (S2448), and 4EBP1 (S65); P < 0.01, P = 0.02, and P = 0.01, respectively]. Similar results were also seen between liver metastases and primary breast tumors [AKT (S473) P < 0.01, mTOR (S2448) P < 0.01, 4EBP1 (S65) P = 0.01]. This signature was lost when primary tumors were compared with all metastatic sites combined.Conclusions: Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of PIK3CA mutations and activation of the PI3K-AKT-mTOR signaling network. Clin Cancer Res; 23(16); 4919-28. ©2017 AACR.

Multi-omic molecular profiling of pancreatic neuroendocrine tumors.

e15685 Multi-omic Molecular profiling of Pancreatic Neuroendocrine Tumors Authors: Rishi R Patel, Joseph Bender, Quanlin, Dana Pan, Lynn Matrisian, David Halverson, Emanuel Petricoin, Subha Madhavan, Richard Tuli, Michael Pishvaian, Andrew Hendifar; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA Background: Pancreatic Neuroendocrine Tumors (pNETs) are a rare malignancy with an incidence of 2 per 1,000,000. In 2016, the Pancreatic Cancer Action Network and Perthera initiated the Know Your Tumor (KYT) initiative in an effort to improve coordination across clinical spectrums in regards to multi-omic molecular profiling and clinical outcomes data pertaining to pancreatic tumors. We used data collected as part of the KYT effort to describe demographic, clinical and genomic data for pNETs. Methods: From 2015 - 2016, 15 patients with pNET were enrolled in the KYT program, which helped facilitate tissue acquisition, clinical data collection, and multi-omic molecular profiling. Using the data collected, we performed Fisher’s Exact to assess for statistical significance between genetic alterations and histology. Results: 11/15 of our patients were female. 8/15 had metastatic disease at the time of diagnosis, while 5/15 had locally advanced disease at the time of diagnosis. 29 genetic alterations were pathogenic. KMT2D and MEN1 were jointly found in 6/15 of our patients. 5/15 with pathogenic alterations in p53, 2/15 with DAXX, 5/15 with alteration in RB1, and 2/15 with alterations in PTEN and TSC2. 2 patients had pathologic alterations in mismatch repair genes, MLH1 and MSH1. Two genes had a statistically significant relationship to pNET histology. Alterations in MEN1 (p = 0.0097) and SPTA1 (p = 0.0333) were associated with high grade tumors (p = 0.0097). Of note, both of the patients under the age of 35 shared an alteration in ATR, which none of the other enrollees expressed. Conclusions: In PNETS, multi-omic profiling through the KYT program identified targetable alterations in several key pathways. Outcome data will be explored.

LungMATCH: Rates of molecular testing in the lung cancer community.

e20671 Background: For metastatic non-small cell lung cancer (NSCLC), guidelines include molecular testing for actionable biomarkers and recommend broad profile testing. Yet previous studies indicate that not all patients with NSCLC receive testing, even for actionable mutations in EGFR, ALK, and ROS. We hypothesized low testing rates for patients calling a community HelpLine and that we could increase rates with one-on-one caller education and free precision medicine services. Methods: Caller statistics were collected on the toll-free Lung Cancer Alliance (LCA) HelpLine from Sept 1, 2016 – Jan 31, 2017. Recruitment to the LungMATCH molecular testing program began Nov 10, 2017. Patients are recruited through conversations on the LCA HelpLine, then consented into Perthera Cancer Analysis (PCA) through an IRB-approved registry protocol. PCA includes tissue acquisition, multi-omic molecular profiling, and medical review of testing results and clinical and treatment history. PCA reports are returned to both treating physicians and patients. Data is being collected longitudinally on treatment decisions, patient outcomes including progression-free and overall survival, and patient experience. Results: Data from the LCA Helpline identified a gap in molecular testing. 50% (57/115) of patients asked if they received any kind of molecular testing replied "No". Of 32 patients who were tested and knew the results, patients indicated potentially actionable changes in EGFR(15), ALK(8), PD-L1(3), RET, MET, BRAF, and HER2, along with KRAS (4). Since LungMATCH launch, 23 interested patients were referred for PCA. Six patients consented and are undergoing PCA with seven more in the consent process. Reasons for non-consent include: doctor refusal, initiation of testing at the treating institution, concern about financial implications, and one death. Updated results will be presented. Conclusions: Our data indicate that patients with lung cancer are not receiving molecular testing in accordance to guidelines. To address this, we created a program through nonprofit-corporate partnership that navigates patients and their physicians through comprehensive precision therapy. This type of program is feasible and there is patient interest.

Bayesian AI to delineate molecular signatures of patient susceptibility to potential hematologic events in a phase I study of BPM31510 (ubidecarenone) in solid tumors.

e14042 Background: BPM 31510 is a ubidecarenone containing nanodispersion elicits anticancer effect by switching cancer cells energy generation from glycolysis to mitochondrial OXPHOS; i.e. reverses Warburg effect. This Phase 1 study is evaluating safety of 144-hour infusion of BPM 31510 as a single agent and in combination with 3 standard chemotherapy regimens. The molecular adaptive study design enabled longitudinal multi-omic molecular profiling to delineate personalized cause-and-effect networks relating patient biology to clinical outcomes using unbiased Bayesian statistics based bAIcis Artificial Intelligence (AI) technology Methods: Eligible pts (aged ≥ 18 y) were relapsed/refractory to standard therapy. The monotherapy arm received IV BPM31510 for 144-hour infusion in 28d cycles, and combination arms (gemcitabine, 5-FU or docetaxel) were primed with BPM 31510 for 3 wks followed by weekly dosing in a 6wk cycle. Doses were escalated in a 3+3 schema. Endpoints were safety, PK and multi-omics analysis. Clinical information was processed and integrated with multi-omic molecular data (metabolomics, lipidomics and proteomics), utilized bAIcis to learn relationships and extract actionable information from pt records, molecular features and corresponding clinical response. Results: As of 10 Dec 2016, 97 pts have been enrolled. Hematologically-related DLTs were reported at 171mg/kg in monotherapy and 137mg/kg in the BPM31510+gemcitabine arm (maximum administered dose). The bAIcis-generated set of predictors defining coagulation-related events in the clinical trial population include proteins, lipids, and metabolites, the levels of which can potentially predict undesirable events prior to and 24h after the 1st treatment with BPM 31510. Conclusions: BPM31510 is well tolerated as a monotherapy and in combination with chemotherapeutic agents. Molecular signatures of susceptibility have been identified through use of multi-omic based AI analysis. Molecular signatures predictive of coagulation-related events will be assessed in Phase 2 and 3 trials to guide the development plan for BPM 31510 as anticancer agent. Clinical trial information: NCT01957735.

The Know Your Tumor (KYT) initiative: A national program of multi-omic molecular profiling (MoP) for patients (Pts) with pancreatic cancer (PDA).

279 Background: There has been a significant increase in the utilization of MoP to facilitate the selection of therapies for pts with advanced cancers. However, coordinated efforts to perform uniform MoP and collect clinical outcomes data have only successfully been executed in limited academic settings. In an effort to “democratize” the availability of MoP for PDA patients in a broad spectrum of clinical settings, The Pancreatic Cancer Action Network (PanCAN) and Perthera initiated the KYT initiative, an academic, industry, and advocacy group collaboration. Methods: PDA pts self-referred to the Patient Central call center at PanCAN. Pts interested in enrolling in an IRB-approved registry trial were then referred to Perthera to facilitate consent, tissue acquisition, and commercial MoP of the pt’s tumor. Test results were reviewed by a team of PDA specialists in the context of the pt’s treatment (tx) history. A report detailing tx options was delivered to the pt’s oncologist. Pts are being actively followed longitudinally to assess physician acceptance of the tx options and to track outcomes. Results: From 06/2014 to 09/2015, 382 pts were enrolled into KYT. Of these, 273 pts from 192 physicians (community and academic) in 38 states were enrolled. Reasons for non-enrollment were: pts no longer interested (67%); pts too ill or not appropriate for KYT (17%); the pt’s physician would not sanction MoP (16%). To date, 162 pt tumor samples have been obtained, and 117 reports delivered. 75% of samples had adequate tissue for genomic profiling (NGS), with 87% of samples harboring a KRAS mutation. Actionable findings (i.e. linked to a specific tx option) identified by NGS included mutations in BRCA2 (5%), PALB2 (1%), ATM (4%); BRAF (2%), PIK3C/PIK3R (7%), STK11 (5%), amplification of ERBB2 (3%), FGFR (2%), PDGFR (2%); and RET fusions (2%). Of the 117 profiles, 43% revealed actionable findings; 58% presented off-label therapy options; and 48% led towards high priority clinical trials. Conclusions: MoP of pts with PDA is feasible irrespective of their geographical location or access to an academic center. Updated information on tx selection and patient outcomes will be provided.