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Last Updated: 12/17/18

2018 SPORE Advances

[+] Brain

Frederick Lang, MD — University of Texas/MD Anderson Cancer Center Brain SPORE

Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma.

The Delta-24-RGD adenovirus, a replication competent, tumor specific oncolytic adenovirus with enhanced infectivity for glioblastoma was developed in the MDACC Lang laboratory. Preclinical cellular and molecular studies validated efficacy in glioma and glioma stem cell models demonstrating viral replication and lysis of tumor cells, increase in autophagy, and induction of tumor specific cytotoxic T cell immune-mediated responses. This work led to a Phase 1 dose escalation trial of Delta-24- RGD (DNX-2401) in patients with recurrent GBM which showed safety, viral infection and replication, and immune changes within the tumor. Several dramatic responses in long-term survival were found. Patient samples showed tumor infiltration of CD8+ T cells and induction of immunogenic cell death in tumor cells, purportedly due to both the oncolytic virus and the immune response to virus and tumor antigens.

Lang FF, Conrad C, Gomez-Manzano C, Yung WKA, Sawaya R, Weinberg JS, Prabhu SS, Rao G, Fuller GN, Aldape KD, Gumin J, Vence LM, Wistuba I, Rodriguez-Canales J, Villalobos PA, Dirven CMF, Tejada S, Valle RD, Alonso MM, Ewald B, Peterkin JJ, Tufaro F, Fueyo J. J Clin Oncol. 2018 May 10;36(14):1419-1427. PMID: 29432077.

[+] Breast

C. Kent Osborne, MD — Baylor College of Medicine Breast SPORE

CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation.

Preclinical experiments tested the use of CAR T cells directed against mucin1 (MUC1) co-expressed with an inverted cytokine receptor linking the IL4 receptor exodomain with the IL7 receptor endodomain (4/7ICR). Results revealed the combination of these signals transforms the suppressive IL4 signal into one that would enhance the anti-tumor effects of CAR T cells at the tumor site leading to T cell expansion, tumor control, in vivo persistence, and memory formation.

Bajgain P, Tawinwung S, D'Elia L, Sukumaran S, Watanabe N, Hoyos V, Lulla P, Brenner MK, Leen AM, Vera JF. J Immunother Cancer. 2018 May 10;6(1):34. PMID: 29747685.

[+] Gastrointestinal

Sanford Markowitz, MD, PhD — Case Western Reserve University GI Cancer SPORE

Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett's esophagus.

Researchers reported a biomarker-based non-endoscopic method for detecting Barrett's Esophagus based on detecting methylated DNAs retrieved via a swallowable balloon-based sampling device. They found that combining two biomarkers (DNA methylation of the CCNA1 and VIM genes) was 95% sensitive and 91% specific in a cohort of 173 individuals.

Moinova HR, LaFramboise T, Lutterbaugh JD, Chandar AK, Dumot J, Faulx A, Brock W, De la Cruz Cabrera O, Guda K, Barnholtz-Sloan JS, Iyer PG, Canto MI, Wang JS, Shaheen NJ, Thota PN, Willis JE, Chak A, Markowitz SD. Sci Transl Med. 2018 Jan 17; 10(424). PMID: 29343623.

Evaluation of patients with an apparent false positive stool DNA test: the role of repeat stool DNA testing.

A stool DNA trial addressed interpretation of positive stool DNA tests when a colonoscopy is negative. Results showed that a positive stool DNA test a year later is likely an indicator for a repeat colonoscopy. A publication describing the recent American Cancer Society screening guidelines, which suggests screening begin at age 45, included a discussion of this SPORE finding.

Cooper GS, Markowitz SD, Chen Z, Tuck M, Willis JE, Berger BM, Brenner DE, Li L. Dig Dis Sci. 2018 Jun;63(6):1449-1453. PMID: 29516325.

Inter-SPORE Collaboration:
Alison Klein, MHS, PhD — Johns Hopkins University GI SPORE
Gloria Petersen, PhD and Daniel Billadeau, PhD — Mayo Clinic, Rochester Pancreatic Cancer SPORE

Detection and localization of surgically resectable cancers with a multi-analyte blood test.

These investigators developed a blood test that can detect eight cancer types (ovary, liver, stomach, pancreas, esophagus, colorectum, lung, and breast) by assessing the levels of circulating proteins and mutations in cell-free DNA. This test, called CancerSEEK, was positive in a median of 70% of the eight cancer types and had sensitivities ranging from 69-98% in five cancer types (ovary, liver, stomach, pancreas, and esophagus). CancerSEEK was also able to localize the cancer to a small number of anatomic sites in a median of 83% of the patients.

Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, Danilova L, Douville C, Javed AA, Wong F, Mattox A, Hruban RH, Wolfgang CL, Goggins MG, Dal Molin M, Wang TL, Roden R, Klein AP, Ptak J, Dobbyn L, Schaefer J, Silliman N, Popoli M, Vogelstein JT, Browne JD, Schoen RE, Brand RE, Tie J, Gibbs P, Wong HL, Mansfield AS, Jen J, Hanash SM, Falconi M, Allen PJ, Zhou S, Bettegowda C, Diaz LA Jr, Tomasetti C, Kinzler KW, Vogelstein B, Lennon AM, Papadopoulos N. Science. 2018 Feb 23;359(6378):926-930. PMID: 29348365.

Adam Bass, MD and Nabeel Bardeesy, MD — Dana-Farber/Harvard GI SPORE

Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition.

A significant percentage of stomach and esophageal cancers have focal amplification of the wild type KRAS gene. While MEK inhibition is often used as a therapy for cancers driven by KRAS, this study from the DF/HCC Gastrointestinal SPORE showed that cancers driven by amplification of wild-type KRAS are resistant to MEK inhibitors such as trametinib. However, targeting both the KRAS activator SHP2 along with MEK was efficacious for amplified KRAS cancers in preclinical models.

Wong GS, Zhou J, Liu JB, Wu Z, Xu X, Li T, Xu D, Schumacher SE, Puschhof J, McFarland J, Zou C, Dulak A, Henderson L, Xu P, O'Day E, Rendak R, Liao WL, Cecchi F, Hembrough T, Schwartz S, Szeto C, Rustgi AK, Wong KK, Diehl JA, Jensen K, Graziano F, Ruzzo A, Fereshetian S, Mertins P, Carr SA, Beroukhim R, Nakamura K, Oki E, Watanabe M, Baba H, Imamura Y, Catenacci D, Bass AJ. Nat Med. 2018 Jul;24(7):968-977. Erratum in: Nat Med. 2018 Oct; 24(10):1627. PMID: 29808010.

[+] Hyperactive RAS

D. Wade Clapp, MD and Kevin Shannon, MD — Indiana University Hyperactive RAS Tumor SPORE

Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis.

Neurofibromatosis type 1 associates with multiple neoplasms, and the Schwann cell tumor neurofibroma is the most prevalent. New data indicate that prevention of inflammation and possibly also nerve injury at the observed tumor locations are therapeutic approaches for neurofibroma prophylaxis and that such treatment should be explored.

Liao CP, Booker RC, Brosseau JP, Chen Z, Mo J, Tchegnon E, Wang Y, Clapp DW, Le LQ. J Clin Invest. 2018 Jul 2;128(7):2848-2861. PMID: 29596064.

Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of childhood caused by mutations in the Ras pathway. Outcomes in JMML vary markedly from spontaneous resolution to rapid relapse after hematopoietic stem cell transplantation. This study indicates that DNA methylation patterns in JMML are predictive of outcome and can identify the patients most likely to experience spontaneous resolution.

Stieglitz E, Mazor T, Olshen AB, Geng H, Gelston LC, Akutagawa J, Lipka DB, Plass C, Flotho C, Chehab FF, Braun BS, Costello JF, Loh ML. Nat Commun. 2017 Dec 19;8(1):2127. PMID: 29259179.

[+] Lung

Robert Doebele, MD, PhD and Paul Bunn Jr., MD — University of Colorado Cancer Center Lung Cancer SPORE

Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children.

Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or tumor type. The Colorado Lung Cancer SPORE generated and provided a unique cell line that was used in the screen for the agent. Larotrectinib was issued an orphan drug status and was granted Priority Review by the FDA earlier this year followed by a full approval for solid tumors with NTRK gene fusions. This is the second tissue-agnostic FDA approval of an anti-cancer targeted therapy.

Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, Nathenson M, Doebele RC, Farago AF, Pappo AS, Turpin B, Dowlati A, Brose MS, Mascarenhas L, Federman N, Berlin J, El-Deiry WS, Baik C, Deeken J, Boni V, Nagasubramanian R, Taylor M, Rudzinski ER, Meric-Bernstam F, Sohal DPS, Ma PC, Raez LE, Hechtman JF, Benayed R, Ladanyi M, Tuch BB, Ebata K, Cruickshank S, Ku NC, Cox MC, Hawkins DS, Hong DS, Hyman DM. N Engl J Med. 2018 Feb 22; 378(8):731-739. PMID: 29466156.

John Minna, MD and Jack Roth, MD — University of Texas Southwestern (UTSW)/MD Anderson Cancer Center (MDACC) SPORE in Lung Cancer

Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.

The UTSW/MDACC Lung Cancer SPORE investigators designed a new chemistry-driven de novo discovery strategy tailored for coincident delivery of preclinical therapeutic triads. Appropriate context-specific intervention targets, tightly linked to response biomarkers, are coupled to agents to engage these targets. The approach led them to discover novel chemically-addressable vulnerabilities in lung cancer.

McMillan EA, Ryu MJ, Diep CH, Mendiratta S, Clemenceau JR, Vaden RM, Kim JH, Motoyaji T, Covington KR, Peyton M, Huffman K, Wu X, Girard L, Sung Y, Chen PH, Mallipeddi PL, Lee JY, Hanson J, Voruganti S, Yu Y, Park S, Sudderth J, DeSevo C, Muzny DM, Doddapaneni H, Gazdar A, Gibbs RA, Hwang TH, Heymach JV, Wistuba I, Coombes KR, Williams NS, Wheeler DA, MacMillan JB, Deberardinis RJ, Roth MG, Posner BA, Minna JD, Kim HS, White MA. Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer. Cell. 2018 May 3;173(4):864-878.e29. PMID: 29681454.

A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers.

The search for predictive markers to determine response to immunotherapy in lung cancer patients led to the discovery of specific white blood cells that can be used for this purpose. The Yale Lung Cancer SPORE investigators established that dormant tumor infiltrating lymphocytes (TILs) can predict overall survival of patients undergoing checkpoint inhibition therapy and that these cells can be reinvigorated upon PD-1 blockade in a patient-derived xenograft model.

Gettinger SN, Choi J, Mani N, Sanmamed MF, Datar I, Sowell R, Du VY, Kaftan E, Goldberg S, Dong W, Zelterman D, Politi K, Kavathas P, Kaech S, Yu X, Zhao H, Schlessinger J, Lifton R, Rimm DL, Chen L, Herbst RS, Schalper KA. Nat Commun. 2018 Aug 10;9(1):3196. PMID: 30097571.

[+] Myeloma

Kenneth Anderson, MD — Dana-Farber/Harvard Cancer Center Myeloma SPORE

Genomic patterns of progression in smoldering multiple myeloma.

This report shows that the genomic landscape, including mutational profile and structural rearrangements, at the pre-cancerous smoldering stage is very similar to Multiple Myeloma (MM). Paired sample analysis shows two different patterns of progression: a "static progression model," where the subclonal architecture is retained as the disease progressed to MM; and a "spontaneous evolution model," where a change in the subclonal composition is observed. These results provide a unique insight into myelomagenesis with potential implications for the definition of smoldering disease and timing of treatment initiation.

Bolli N, Maura F, Minvielle S, Gloznik D, Szalat R, Fullam A, Martincorena I, Dawson KJ, Samur MK, Zamora J, Tarpey P, Davies H, Fulciniti M, Shammas MA, Tai YT, Magrangeas F, Moreau P, Corradini P, Anderson K, Alexandrov L, Wedge DC, Avet-Loiseau H, Campbell P, Munshi N. Nat Commun. 2018 Aug 22;9(1):3363. PMID: 30135448.

[+] Ovarian

Kunle Odunsi, MD, PhD — Roswell Park Cancer Institute Ovarian SPORE

Rapid construction of antitumor T-cell receptor vectors from frozen tumors for engineered T-cell therapy.

Investigators from the Roswell Park Cancer Institute Ovarian SPORE developed a method to construct a T-cell receptor (TCR)-expressing library from specimens that contain antigen-specific T cells, including frozen tumor biopsies. They were able to engineer peripheral T-cells from a library-derived TCR-gene with demonstrated antitumor effects in a tumor xenograft model. This method could potentially be used to manufacture therapeutic and personalized anti-tumor T-cell product.

Tsuji T, Yoneda A, Matsuzaki J, Miliotto A, Ryan C, Koya RC, Odunsi K. Cancer Immunol Res. 2018 May;6(5):594-604. PMID: 29588318.

[+] Prostate

Inter-SPORE Collaboration:
Arul Chinnaiyan, MD, PhD and Ganesh Palapattu, MD — University of Michigan SPORE in Prostate Cancer
Peter Nelson, MD — Fred Hutchinson Cancer Center/Pacific Northwest Prostate Cancer SPORE

Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer.

This publication shows that inactivating mutations of both alleles of the CDK12 gene defines a distinct subtype of metastatic castration-resistant prostate cancer. CDK12 loss is associated with genomic instability and leads to increased neoantigen burden and T cell infiltration. A subset of patients with CDK12 mutant tumors benefit from immune checkpoint inhibition.

Wu YM, Cieślik M, Lonigro RJ, Vats P, Reimers MA, Cao X, Ning Y, Wang L, Kunju LP, de Sarkar N, Heath EI, Chou J, Feng FY, Nelson PS, de Bono JS, Zou W, Montgomery B, Alva A; PCF/SU2C International Prostate Cancer Dream Team, Robinson DR, Chinnaiyan AM. Cell. 2018 Jun 14;173(7):1770-1782.e14. PMID: 29906450.