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2023 AWARDS

NEW GRANT
Richard Gorlick, M.D.- Division Head- The University of Texas- MD Anderson Cancer Center

Developing novel antibody drug conjugates for the treatment of osteosarcoma

The recognition of the potential effectiveness of DS-7300a in the treatment of osteosarcoma has led to a phase 2 clinical trial for patients with recurrent osteosarcoma in Europe. Recognizing that the differential target protein expression, between osteosarcoma and normal human tissues, was higher for some proteins that did not have drugs already made raised the possibility that even greater therapeutic potential could be realized. A novel antibody drug conjugate was created using an antibody which exists targeting CADM1 as a proof of principle. The tool compound antibody drug candidate had numerous desirable properties, showing dramatic effectiveness in preclinical models for the treatment of osteosarcoma. Continued work will move this beyond a tool compound and produce an antibody drug conjugate, targeting CADM1 which can be administered to patients with osteosarcoma as part of a clinical trial.

Yifei Wang, Zhongting Zhang, Wendong Zhang, Xiangjun Tian, Rossana Lazcano, Michael Roth, Jonathan Gill, Douglas Harrison, Zhaohui Xu, Yizheng Tu, Sylvester Jusu, Giuseppe Longo, Xin Zhou, Jing Wang, Richard Gorlick. Targeting cell adhesion molecule 1 (CADM1) with an antibody drug conjugate for the treatment of osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1202.

2022 AWARDS

NEW GRANT
Richard Gorlick, M.D.- Division Head- The University of Texas- MD Anderson Cancer Center

Recognition and optimization of antibody drug conjugates for the treatment of osteosarcoma

With the initial proof of principle that antibody drug conjugates may be an effective treatment strategy for patients with osteosarcoma, review of other proteins identified in the surfaceome profiling revealed other opportunities. Some identified surface proteins were associated with existing antibody drug conjugates, some were associated with antibodies which has never been made into drugs and others never had antibodies targeting them. Particularly noteworthy was the expression of B7H3, also known as CD276 as a potential surface drug. The expression of this protein provided the opportunity that multiple antibody drug conjugates had already been developed targeting it. This allowed an exploration of the effect of differing payloads on the effectiveness of the antibody drug conjugate. This allowed a recognition that DNA damaging agents were the most effective payloads, with DS-7300a being the most effective drug in preclinical models for the treatment of osteosarcoma.

Kendsersky NM, Lindsay J, Kolb EA, Smith MA, Teicher BA, Erickson SW, Earley EJ, Mosse YP, Martinez D, Pogoriler J, Krytska K, Patel K, Groff D, Tsang M, Ghilu S, Wang Y, Seaman S, Feng Y, Croix BS, Gorlick R, Kurmasheva R, Houghton PJ, Maris JM. The B7-H3-Targeting Antibody-Drug Conjugate m276-SL-PBD Is Potently Effective Against Pediatric Cancer Preclinical Solid Tumor Models. Clin Cancer Res. 2021 May 15;27(10):2938-2946. doi: 10.1158/1078- 0432.CCR-20-4221. Epub 2021 Feb 22. PMID: 33619171; PMCID: PMC8127361. Richard Gorlick, E. Anders Kolb, Yifei Wang, Peter Houghton, Raushan Kurmasheva, Yael Mosse, John Maris, Matthew Tsang, David Groff, Kateryna Krytska, Xiao-Nan Li, Yuchen Du, Jun Hasegawa, Nanae Izumi, Steven Neuhauser, Anuj Srivastava, Tim Stearns, Vivek Philip, Emily L. Jocoy, Jeff Chuang, Carol J. Bult, Beverly Teicher, Malcolm Smith. Evaluation of the in vivo efficacy of the B7-H3 targeting antibody-drug conjugate (ADC) DS7300a: A report from the Pediatric Preclinical In Vivo Resting (PIVOT) program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB061.

2021 AWARDS

NEW GRANT
Richard Gorlick, M.D.- Division Head- The University of Texas- MD Anderson Cancer Center

Our 2021 funding led to the listed publication, published in 2022

Surfaceome Targeting with Antibody Drug Conjugates A pipeline was established to identify proteins expressed both frequently and abundantly on the surface of osteosarcoma cells, but not on normal tissues. It was hypothesized that these proteins would exist related to osteosarcoma retaining its normal property of producing bone. A series of proteins abundantly expressed on osteosarcoma were identified. Some of these proteins had drugs which targeted them, specifically antibody drug conjugates. Antibody drug conjugated work by tethering a drug payload to an antibody which will be internalized when it binds to the protein on the surface of a cell. As a proof of principle we utilized an antibody drug conjugate targeting MMP14 to show that this approach was feasible and potentially effective.

Wang Y, Tian X, Zhang W, Zhang Z, Lazcano R, Hingorani P, Roth ME, Gill JD, Harrison DJ, Xu Z, Jusu S, Kannan S, Wang J, Lazar AJ, Earley EJ, Erickson SW, Gelb T, Huxley P, Lahdenranta J, Mudd G, Kurmasheva RT, Houghton PJ, Smith MA, Kolb EA, Gorlick R. Comprehensive Surfaceome Profiling to Identify and Validate Novel Cell-Surface Targets in Osteosarcoma. Mol Cancer Ther. 2022 Jun 1;21(6):903-913. doi: 10.1158/1535-7163.MCT-21-0836. PMID: 35312779; PMCID: PMC916771

2020 AWARDS

NEW GRANT
Richard Gorlick, M.D.- Division Head- The University of Texas- MD Anderson Cancer Center

Our 2020 funding (together with our 2019 funding) combined into the recently final 2020 published study:

Immuno-genomic landscape of osteosarcoma

Limited clinical activity has been seen in osteosarcoma (OS) patients treated with immune checkpoint inhibitors (ICI). To gain insights into the immunogenic potential of these tumors, we conducted whole genome, RNA, and T-cell receptor sequencing, immunohistochemistry and reverse phase protein array profiling (RPPA) on OS specimens from 48 pediatric and adult patients with primary, relapsed, and metastatic OS. Median immune infiltrate level was lower than in other tumor types where ICI are effective, with concomitant low T-cell receptor clonalities. Neoantigen expression in OS was lacking and significantly associated with high levels of nonsense-mediated decay (NMD). Samples with low immune infiltrate had higher number of deleted genes while those with high immune infiltrate expressed higher levels of adaptive resistance pathways. PARP2 expression levels were significantly negatively associated with the immune infiltrate. Together, these data reveal multiple immunosuppressive features of OS and suggest immunotherapeutic opportunities in OS patient.

Futreal et al. Immuno-genomic landscape of osteosarcoma
MD Anderswon Cancer Center, Houston, Texas, USA, 2020 Click here to view his Article...

2019 AWARDS

NEW GRANT
Richard Gorlick, M.D.- Division Head- The University of Texas- MD Anderson Cancer Center

Our 2019 funding initiated the primary tools needed to undertake a major group effort examining the limited immunogenic effects of checkpoint inhibitors (ICI) on Osteosarcoma. Dr. Gorlick's lab at MD Anderson did multiple individual sub-studies that were part of the overall aim: to examine if a role for a directed immunological based attack on osteosarcoma is possible. His lab's work could be summarized:

Surfaceome Profiling of Osteosarcoma: Yifei Wang, "The Stacey Leondis Swim Across America Research Fellow" primary project has been to identify the most abundant surface proteins on osteosarcoma. Through comparing those to proteins known to be on normal cells the study has identified a series of potential drug targets. They are expanding the number of osteosarcomas profiled to refine the result.

Bar-coding as a means of understanding clonality of osteosarcoma drug resistance: Bar-coding is a new methodology to uniquely tag every cell in an entire tumor. This method is being used to understand which malignant cells are able to survive despite chemotherapy treatment and how they do so. This will help guide future treatment options and improve outcomes.

Identification of approaches to target novel proteins on the surface of osteosarcoma: Dr. Gorlick's lab has confirmed that a number of the targets identified on the surface of osteosarcoma are abundantly expressed in virtually all osteosarcomas and to a very limited extent on normal tissue. Some of these are not known at present to be drug targets. The lab is making antibodies to be able to target these proteins with antibodies and cell therapy approaches.

2018 AWARDS

NEW GRANT
Richard Gorlick, M.D.- Division Head- The University of Texas- MD Anderson Cancer Center
Proteins on the cell surface of osteosarcoma cells can be targeted with immunotherapy. This study focuses on identifying proteins uniquely expressed on osteosarcoma cells with the goal developing antibody drug-conjugates and chimeric antigen receptor T-cells directed against these targets. Utilizing mass spectrometry and RNASeq a number of potential targets have been identified and target selection is being finalized for the creation and testing of new immunotherapies in the Gorlick Lab.

NEW GRANT
Richard Gorlick, M.D.- Division Head- The University of Texas- MD Anderson Cancer Center
Numerous targeted agents have been developed by the pharmaceutical industry for many types of cancer. The Gorlick lab has an extensive number of osteosarcoma mouse models that are being utilized to pre-screen drugs that have high potential to be effective in patients with osteosarcoma. The Gorlick lab has been genomically characterizing osteosarcoma mouse models in an effort to match the models with specific genomic alterations with relevant targeted therapies to assess the efficacy of “matched” therapy.

NEW GRANT
Richard Gorlick, M.D.- Division Head- The University of Texas- MD Anderson Cancer Center
Immunotherapies, including checkpoint inhibitors, which allow patients’ immune systems to recognize cancer cells as abnormal and clear the tumors have been effective treatments for a number of malignancies. The Gorlick labs is establishing mouse models of osteosarcoma that have intact immune systems in order to evaluate the efficacy of checkpoint inhibitors and other immunotherapies in pre-clinical models, prior to bringing these agents to clinical trials in children and adolescents.

2017 AWARDS

NEW GRANT
Richard Gorlick, M.D.- Division Head- The University of Texas- MD Anderson Cancer Center
This study examined the safety of giving supplemental Bone Morphogenetic Protein-2 as a treatment to enhance the adhesion of allograft-host unions which is needed for recovery following limb salvag surgery for osteosarcoma patients.

NEW GRANT
Richard Gorlick, M.D.- Division Head- The University of Texas- MD Anderson Cancer Center
HHLA2 is a new checkpoint inhibitor (a co T cell inhibitor) in the same family as PD-L1/PD-1 and this study examines its presence in osteosarcoma. The results of this study suggested some primary and most metastatic OS disease express this protein. This suggests this may be a relevant immunosuppressive mechanism in the OS tumor microenvironment.

2016 AWARDS

NEW GRANT
Richard Gorlick, M.D.- The Childrens's Hospital at Montefiore, Bronx, New York
This study examined the prognostic significance of PD-L1 expression and immune cell(s) infiltration in osteosarcoma. It also started the investigation into the correlation of PD-1 and/or PD-L1 expression and immune cell infiltration with 5 year EFS (event free survival) outcomes.

NEW GRANT
Richard Gorlick, M.D.- The Childrens's Hospital at Montefiore, Bronx, New York
This study attempted to better define the cellular origin of osteosarcoma using a mouse model. Osteoarcoma is believed to develop from a cell that is in the process of differentiating from a MSC (mesenchymal stem cell) to a pOB (preosteoblast).

2015 AWARDS

CONTINUED FUNDING
Awarded in 2010 The Swim Across America Foundation of Nassau and Suffolk
“Stacey Leondis Fellowship at The Children’s’ Hospital at Montefiore”, Bronx, New York.
This annual support is given in Stacey's memory for a fellowship to further the osteosarcoma research effort in the laboratory of Dr. Richard Gorlick.

CONTINUED FUNDING
Richard Gorlick, M.D.- The Childrens's Hospital at Montefiore, Bronx, New York
Targeting the insulin-like growth factor receptor – With osteosarcoma clearly associated with normal human growth a focus of the Gorlick Laboratory has continued to be targeting this pathway with various drugs. Two pivotal clinical trials are ongoing now testing these drugs in sarcoma patients. A new concept targeting another member of this signaling pathway – IGF-2R- has yielded promising results.

CONTINUED FUNDING
Richard Gorlick, M.D.- The Childrens's Hospital at Montefiore, Bronx, New York
The study of GD2 directly led to a study of dinutuximab (ch14.18 antibody) by the Children’s Oncology Group in patients with recurrent osteosarcoma which opened to patient accrual on November 30, 2015. The study of GPNMB supported a study of glembatumumab vedotin which will be performed by the Children’s Oncology Group with planned activation in early 2016.

NEW GRANT
Richard Gorlick, M.D.- The Childrens's Hospital at Montefiore, Bronx, New York
Building upon work demonstrating the effectiveness of immune checkpoint inhibitors in the treatment of melanoma defined by genomic complexity, which is similarly present in osteosarcoma, the Gorlick Laboratory is initiating studies investigating the therapeutic relevance of these drugs. Effectiveness of these agents are driven by the presence of immune infiltrates as well as PD-1/PD-L1 expression which will be investigated with the support of the FOSTER foundation. These studies have the potential to identify these drugs as potentially effective in osteosarcoma driving clinical trials as previous studies have accomplished in the past.

CONTINUED FUNDING
Rachel L. Flynn, Assistant Professor, Department of Pharmacology & Experimental Therapeutics and Medicine, Division of Hematology and Medical Oncology, Boston University School of Medicine
Probing the Alternative Lengthening of Telomeres (ALT) Pathway in Osteosarcoma
In order for a normal cell to remain a cancer cell, a number of changes need to occur with one of them being maintaining the length of chromosomes, whose ends are called telomeres, through multiple cycles of cell division. Although most cancers stabilize their chromosomes through activating an enzyme called telomerase, others use a less well understood process called alternative lengthening of telomeres or ALT. The challenge with ALT is although drugs have been developed to inactivate telomerase, drugs have not previously been discovered that inhibit ALT. In work supported by the FOSTER foundation, the Flynn laboratory has shown that osteosarcoma uses ALT and coupled to how these cells correct DNA errors, a therapeutic vulnerability is revealed. Furthermore the Flynn Laboratory has discovered drugs which inhibit ALT which are needed to treat this class of tumors. The magnitude of this drug discovery yielded a publication in the high profile journal, Science. We anticipate with time this may yield new and improved treatments for osteosarcoma.

2014 AWARDS

CONTINUED FUNDING
Awarded in 2010 The Swim Across America Foundation of Nassau and Suffolk
“Stacey Leondis Fellowship at The Children’s’ Hospital at Montefiore”, Bronx, New York.
This annual support is given in Stacey's memory for a fellowship to further the osteosarcoma research effort in the laboratory of Dr. Richard Gorlick.

CONTINUED FUNDING
Rachel L. Flynn, Assistant Professor, Department of Pharmacology & Experimental Therapeutics and Medicine, Division of Hematology and Medical Oncology, Boston University School of Medicine
Probing the Alternative Lengthening of Telomeres (ALT) Pathway in Osteosarcoma

NEW GRANT
Variable Expression of Argininosuccinate Synthetase Protein and Correlation with Novel Therapeutic ADI-PEG20 in Osteosarcoma
Richard Gorlick, M.D.- The Childrens's Hospital at Montefiore, Bronx, New York
The amino acid arginine is involved in protein synthesis and tumor metabolism and is essential for the growth of human cancer cells. Pegylated arginine deaminase (ADI-PEG20) is a novel therapy that lowers extracellular arginine levels and has shown evidence of clinical efficacy and low toxicity in patients with tumors lacking argininosuccinate synthetase (ASSl) protein expression. Previous studies have demonstrated the effectiveness of ADI-PEG20 in cancer cell lines with diminished or absent ASS1 protein including melanoma and hepatocellular carcinoma. Breast cancer and lung cancer cell lines, both of which frequently maintain strongly positive ASS1 protein expression, continued to proliferate in the presence of ADI-PEG20. ADI-PEG20 sensitivity has not been previously evaluated in osteosarcoma.

CONTINUED FUNDING
The Osteosarcoma Genome Project
Marc Ladanyi, M.D., Paul Meyers, M.D. John Healey, M.D. - Memorial Sloan Kettering Cancer Center-New York, New York
Awarded in 2010: Osteosarcoma is not currently a focus of federally supported cancer genomics efforts such as The Cancer Genome Atlas. Our study will comprehensively screen the genome of both pediatric and adult Osteosarcomas for cancer causing mutations. Genomic technologies have advanced rapidly in recent years, making it possible to completely screen all genes in a given tumor sample for mutations. Screening of even a small number of samples of a given cancer type can yield important discoveries. The uniqueness of this study is that the analysis is coming from patients tumors at different stages of their disease i.e. not only biopsies.