Multiple Molecular Subtypes of Sarcoma Allow for Orphan Drug Development

The Journal of Targeted Therapies in Cancer2016 October
Volume 5
Issue 5

Van Tine examines the most attractive molecular targets in sarcoma and the current state of drug development.



The treatment of sarcomas is complicated by the fact that we have historically treated them as 1 single disease entity. Presently, the term sarcoma represents over 100 separate diseases, each with multiple molecular subtypes and underlying biology. Under the rubric of orphan drug development, each molecular subtype, whether by biomarker or gene signature, may allow for targeted drug development. As we biologically subdivide the sarcomas, more clinical trials are needed to advance the treatment of rare cancers. The sarcoma field has matured in the last 5 years to become a clinical trialist community that is well organized to perform rapid phase III clinical trials. The field is also able to conduct trials in rare or focused subgroups in an efficient fashion using collaborative group mechanisms such as the Sarcoma Alliance for Research and Collaboration (SARC). In this review, we will examine the most attractive molecular targets in sarcoma and the current state of drug development.




Sarcoma is a group of well over 100 different diseases that only have their mesenchymal origin in common.This is a family of tumors that arise from fat, muscle, bone and cartilage.Although it is often categorized as one disease, in reality it is an aggregate of many molecular and pathologic separate subtypes of sarcoma.

It is interesting that the parallel to sarcoma is carcinoma. Our colleagues who treat carcinomas are not referred to as carcinoma doctors; instead they refer to themselves as breast cancer, lung cancer, colon cancer, etc. oncologists. As sarcoma doctors, we take over 100 different diseases with their individual subtypes and often lump them into 1 group. This does a great disservice to a disease whose biological diversity and well-known underlying genetics are therapeutic opportunities for drug development. In addition, it has likely been this all-inclusive approach to sarcoma that has led to the lack of positive phase III trials in all-comer sarcoma trials.



One of the things that makes sarcomas different from carcinomas is that they have a propensity fibrosis, as opposed to shrinking and disappearing, when there is a chemotherapy response.Though the propensity to fibrose is variable, some histologies, such as synovial sarcomas in some patients do respond, this may be related to the amount of matrix associated with each tumor. As such, trials looking at response rate (RR), which counts only complete and partial responses, instead of clinical benefit rate (CBR), which also includes stable disease, are hindered by a lack of appreciation for mesenchymal biology. The appreciation of fibrosis has changed the metric for drug approval in sarcoma,as progression-free survival (PFS) and overall survival (OS) metrics are better measures of trial outcomes for sarcoma patients.





In the last 5 years, there have been many phase III clinical trials for soft tissue sarcomas.The most important of which may be the clinical trial using ridaforlimus (Taltorvic) for maintenance therapy after chemotherapy in soft tissue sarcoma.Of interest, this clinical trial was able to demonstrate a statistically significant 3-week OS compared to placebo. While this may be a clinically meaningless result, the reason for the OS benefit was never explained, because there was no correlative biomarker work explored in this clinical trial. What makes this trial so important is that it was a 711-patient trial that accrued in approximately 2 years, which demonstrated clearly that the sarcoma community could conduct large trials efficiently. This was followed by 2 other rapidly accruing clinical trials, ZIO-201 (palifosfamide) and TH302 (evofosfamide). While both of these rapidly accrued, they did not demonstrate PFS or OS. Next, a large phase III trial was performed in Europe using pazopanib for the treatment of non-liposarcoma soft tissue sarcoma (STS) that led to the FDA approval based on PFS, but not OS. The broad spectrum of tyrosine kinase inhibition of pazopanib (Votrient) may explain why there was a positive PFS amongst a large selection of multiple subtypes of sarcomas.More recently, another large phase III clinical trial of aldoxirubicin also rapidly accrued, most likely due to patient selection and trial design, but failed to demonstrate the predetermined trial endpoints at this time.These trials were all complicated by the all-comer study design.



Two other drugs have been recently approved by the FDA based on phase III trials, but these trials were histology focused. The first trial was of trabectedin, which was a phase III trial in leiomyosarcoma (LMS) and liposarcoma, and was granted FDA approval based on its secondary aim of PFS.Though this drug is used to treat many types of high-grade sarcomas, the investigators tailored this trial to 2 well-known responding histologies for approval in the USA. Even with this approach, the study failed to meet its primary objective, which was OS. In parallel, eribulin (Halaven) was also studied in a phase III trial in the same patient population.While it was found to be no better than dacarbazine in terms of PFS, it was found to have an OS driven by the liposarcoma arm of the trial, and as such was approved for liposarcoma by the FDA. Neither of these studies truly accounted for the molecular heterogeneity of LMS or the 5 separate subtypes of liposarcoma which all have diverse underlying molecular biology.


As will be discussed below, the underlying molecular knowledge of the sarcoma subtypes represents an extensive literature, which when exploited, can be used for orphan-drug development. In this review, we will look at the most promising therapeutic targets found in the sarcoma subtypes. We will also look at current clinical trials and clinical trial opportunities that are promising in the rare tumor field.

In 1998, the National Institutes of Health held a Biomarkers Definitions Working Group. They defined a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”12 This is the term we will use to identify targets for drug exploration in the rare tumor space. By examining either specific genes, gene mutations or even, possibly, gene signatures, we can partner with industry to design clinical trials based on molecular features as opposed to histology.

TP53Mutations Are Common



ASS1Gene Silencing

Historically, the most common hallmark of sarcoma and its most common biomarker are mutations inTP53.Mutations inTP53can vary widely by subtype from as low as 20% to as high as 90% in osteosarcoma. This is a very important biomarker to understand in the sarcomas due to its relationship with genetic predisposition syndromes. Patients who are found to haveTP53mutations upon tumor screening should also be screened for germline predispositions. The main syndrome to look for is Li-Fraumeni ( the era of genetic tumor screening, one must remember to check the germline when suspicious mutations associated with genetic predispositions are seen in tumors.





One of the few biomarkers in sarcoma that crosses most histologies is the loss of expression of Argininosuccinate Synthetase 1 (ASS1).This gene is silenced by methylation in up to ~90% of most sarcomas. This causes a defect in the urea cycle and renders sarcomas unable to make their own source of arginine. This can be therapeutically exploited using PEGylated arginine deiminase (ADI-PEG 20).The lack ofASS1expression causes arginine dependent tumors to stop growing when they are deprived of the amino acid arginine. Current research is looking at synthetic lethal combinations to use with ADI-PEG 20 that will be highly effective for the treatment of sarcomas and other tumors.

PI3K Mutations and Loss of PTEN Expression

PDGFRα Biology in Sarcomas

PTEN loss is one of the most commonly disrupted tumor suppressors in cancer.20 Recent work has demonstrated that althoughPIK3CAmutations are relatively rare in sarcoma, PTEN loss was demonstrated in 32.2% of non-uterine LMS and 37.6% of uterine LMS.21 This opens up the possibility for biomarker driven trials that target thePIK3CAand mTOR pathways. Currently, a dual mTORC1/mTORC2 inhibitor MLN0128 (Sapanisertib), is in a clinical trial (NCT02601209) for metastatic soft tissue sarcoma.




The platelet-derived growth factor receptor alpha (PDGFRa) is a tyrosine kinase that has been implicated in bone marrow development, migration, chemotaxis, cell survival, and angiogenesis.PDGFRα is expressed in about 33% of soft tissue sarcomas.A recent randomized phase II study using a monoclonal antibody against PDGFRa demonstrated an 11.8 month OS when used in combination with doxorubicin, but not when used sequentially.This may be the growth-factor pathway in sarcomas that would parallel theEGFR, HER2, HER3andHER4pathways seen in carcinomas. Alternatively, this drug may alter the stromal microenvironment altering the ability of sarcomas to progress. The placebo-controlled phase III trial is underway and will determine the importance of this pathway in sarcoma (NCT02451943). Clear mechanistic studies are needed to understand the effects of PDGFRa inhibition.

Mutations inKITandPDGFR





CDK4/MDM2/ATRXin Liposarcomas

While well known, mutations incKITandPDGFRαare common driver mutations in gastrointestinal stromal tumors (GISTs).Continued study of tyrosine kinase inhibitors (TKI) and their resistance patterns has led to advances that are now clinical trials for the treatment of GIST. First, masitinib is being developed in phase II and III trials as a second-line therapy after imatinib (NCT01694277).In addition, advances in the understanding of the imatinib resistance mutations that arise in exon 17 has led to a promising new TKI BLU-285, which has activity against exon 17 mutations and the D842V mutatedPDGFRmutation (NCT02508532).In addition, a second drug, crenolanib, is being developed for the treatment of D842V PDGFRαmutations.Further mechanistic insight into TKI resistance in GIST is needed to further prolong OS in the most common form of sarcoma treated in community practice. As such, clinical trial participation by GIST patents is very much needed.







Well-differentiated liposarcoma and dedifferentiated liposarcoma are driven by amplification in chromosome 12q13-15 that contains both CDK4 and MDM2.The sarcoma community has done a number of clinical trials to treat liposarcoma using CDK4 inhibitorsand MDM2 inhibitors.Recent work by Andrew Koff et al demonstrated the importance of basic science to drug development.They have shown that ATRX is required for the CDK4/6 inhibitor palbociclib (Ibrance) to downregulate MDM2.Downregulation of MDM2 by palbociclib suggests that concurrent use of palbociclib with an MDM2 inhibitor may not be the correct strategy. Further investigation into how best to target these drivers is ongoing.

Alternative Lengthening of Telomeres






NY-ESO1 Antigen Expression

The alternative lengthening of telomeres (ALT) is a common mechanism found in sarcoma for maintaining telomere length, which is telomerase independent.This has been demonstrated to occur in undifferentiated pleomorphic sarcomas, pleomorphic and dedifferentiated liposarcomas, osteosarcomas, leiomyosarcomas, etc.Loss of ATRX function has been demonstrated to contribute to the activation of ALTand careful immunohistochemistry study has demonstrated loss of nuclear but not cytoplasmic ATRX in sarcomas.Loss of nuclear expression of ATRX is consistent with cells undergoing ALT. ATRX inhibitors repress ALT, thus making this a highly attractive area for drug development in rare tumors.


Mutations inKDR/VEGFR2

NY-ESO1 a cancer/testis antigen was first identified in 1997 by Chen et al, and it has been the target for immunotherapy approaches since that time.NY-ESO1 is expressed on 80% of synovial sarcomas and the majority of myxoid/round cell liposarcomas (MRCL). There are 2 strategies being exploited at this time targeting this antigen. The first is by Immune Design using a lentiviral-based dendritic cell vaccine with a PD-L1 inhibitor (NCT02609984). The second is by Adaptimmune (NCT01343043) using adoptive immunotherapy with T cells engineered to recognize NY-ESO-1. Further exploration into immunotherapy using this antigen is needed.


RAS—Pathway-Driven Tumors

Angiosarcoma is a complex group of vascular tumors that may be subtyped, at this time, by how they arise (ie, primary breast, radiation induced, head and neck, etc). A subset of breast angiosarcoma has activating mutations inKDR/VEGFR2.Though rare, this highlights the importance of understanding the underlying biology of the sarcomas. In addition, this highlights the need for patients to be seen by physicians that have the depth of knowledge and experience in sarcoma to know when to look for specific targetable alterations.






Patients with neurofibromatosis type 1 (NF1) carryRAS-activating path mutations in neurofibromin.Adults with this genetic syndrome are predisposed to developing malignant peripheral nerve sheath tumors (MPNSTs), whereas children are predisposed to getting brain tumors.The underlying biology of this tumor is similar to that ofRAS-driven pancreatic cancers. The mTOR pathway has been identified as critical to this tumor, though no clinical trial has yet to show efficacy when this pathway is inhibited.Therapeutics that target the downstreamRASpathway are desperately needed. Of interest,HER2was seen as amplified in 5.6% of MPNSTs, though the relationship with the RAS pathway is unknown.




The term chondrosarcoma represents a group of tumors that arise from cartilage. Work by Lu et al demonstrated that approximately 50% of conventional and dedifferentiated chondrosarcoma harbor mutations inIDH1orIDH2.Mutations in isocitrate dehydrogenase (IDH) led to the production of the oncometabolite (R)-2-hydroxyglutarate (2HG).Currently, there is a phase I trial looking at IDH inhibitors that may be promising for the treatment of this disease (NCT02073994).




cMET, also called the hepatocyte growth factor (HGF), is a tyrosine kinase that has been implicated in alveolar soft parts sarcoma (ASPS) and clear cell sarcoma (CCS). ASPS is driven by a translocation of theASPSgene with an ETS transcription factor TFE3 that drives cMET expression.In parallel, clear cell sarcomas harbor anEWS-ATF1translocation that also drives cMET expression.Clinical trials are needed in both of these rare sarcoma subtypes to conclusively determine if cMET inhibition is warranted.





As part of a recently published profiling paper in sarcoma, the most commonly amplified gene that was observed was theEGFRreceptor, which was found to be amplified in 16.9% of all cases.This has been demonstrated to occur in smaller series from as low as 3.5% to as great as 37%.A phase II trial of cetuximab did not demonstrate activity in a trial that stratified forEGFRexpression.WhetherEGFRis the reason for the amplification in 7p12 or if it is a passenger for another gene’s amplification (eg, IGFBP1, IGFBP3, or UPP1) still needs to be clearly investigated.






Clinical Trials Organizations for Therapeutic Development

Tenosynovial Giant Cell Tumor (TGCT)/Pigmented Villonodular Synovitis (PVNS) are rare diseases characterized by inflammation and overgrowth of the lining of joints.This is a locally aggressive disease associated with a high morbidity and a very low mortality as they rarely metastasize.These tumors are driven by a translocation between COL6A3 andCSF1that drives the expression ofCSF1.The production of excessCSF1sets up an autocrine loop driving TGCT/PVNS.This is being targeted usingCSF1inhibitors in clinical trials (NCT02371369 and NCT01643850). The original Phase I trial of PLX3397 demonstrated promising results.These trials clearly represent the opportunity that rare disease indications provide for targeted therapy development based on mechanism.


In approaching rare diseases like sarcomas, there are collaborative group opportunities that allow for rapid accrual of clinical trials. The largest sarcoma specific trials group is the Sarcoma Alliance for Research and Collaboration (SARC) This is a collaborative group comprised of the leading sarcoma groups in the country that is well organized and has run approximately 30 clinical trials from phase I to III. Additionally, the Alliance Experimental Therapeutics Committee has a long history of focusing on rare diseases and has performed a number of sarcoma focused clinical trials. Finally, there are smaller organizations such as the Midwest Sarcoma Trials Partnership (MSTP) are also available to do smaller phase I/II trials. Collectively, the infrastructure is available with experienced investigators to perform rare disease focused clinical trials.

In conclusion, there are a number of molecularly attractive targets for the treatment of sarcoma when biomarkers and histologies are taken into account. This article was not intended to be an all-inclusive list, but to function to highlight the biological diversity of sarcoma and the opportunities that exist for developing therapeutics in rare tumors. Through a partnership between industry and sarcoma biologists, we can make progress only by treating sarcoma as the diverse group of diseases and focusing on molecular and not histologic subtypes. This will allow for the development of targeted therapies under the banner of orphan disease designation.


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