Using Maackia Amurensis Seed Lectin to Target the Podoplanin Receptor as a Functionally Relevant Biomarker to Inhibit the Growth of Oral Squamous Cell Carcinoma and Precancerous Lesions
Phase: EARLY_PHASE1
Conditions: Squamous Cell Carcinoma of Head and Neck
Sponsor: Rowan University

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Title of Project: Using Maackia amurensis seed lectin to target the podoplanin receptor as a 
functionally relevant biomarker to inhibit the growth of oral squamous cell carcinoma and precancerous 
lesions.
Principal Investigator:
___Mahnaz Fatahzadeh_____________________
Co-Investigators: Gary S. Goldberg, Soly Baredes, Evelyne Kalyoussef, Dylan Roden, Rabie Shanti, 
Ghayoour Mir, Eugenio Capitle, Htay Htay Kyi, David Suster, Alan J. Shienbaum 
Locations: Recruiting, consenting, and specimen collection will take place at Rutgers.
Ex vivo analysis will take place at Rowan.
Name
Role on Project   
Mahnaz Fatahzadeh, DMD, MSD. Professor, Rutgers School of Dental Medicine. 
Sample precancerous oral lesions. Administer MASL. Consenting of 
Subjects. Obtains hematoxylin and eosin (H&E) stained and unstained 
specimens of previously diagnosed oral cancer/precancer patients 
who consent to participate in the study. 
Gary S Goldberg, PhD. Associate Professor, Rowan University School of Osteopathic Medicine.
Study coordinator to manage regulatory paperwork, IRB
approvals, and other documents. Evaluate PDPN expression and
 
effects of MASL on oral cancerous and precancerous cells.
Soly Baredes
Sample oral cancers. Administer MASL. Consenting of
Subjects. Obtains hematoxylin and eosin (H&E) stained and unstained 
specimens of previously diagnosed oral cancer/precancer patients 
who consent to participate in the study. 
Evelyne Kalyoussef
Sample oral cancers. Administer MASL. Consenting of
Subjects. Obtains hematoxylin and eosin (H&E) stained and unstained 
specimens of previously diagnosed oral cancer/precancer patients 
who consent to participate in the study. 
Dylan Roden                          Sample oral cancers. Administer MASL. Consenting of
Subjects. Obtains hematoxylin and eosin (H&E) stained and unstained 
specimens of previously diagnosed oral cancer/precancer patients 
who consent to participate in the study. 
Rabie Shanti                          Sample oral cancers. Administer MASL. Consenting of
Subjects. Obtains hematoxylin and eosin (H&E) stained and unstained 
specimens of previously diagnosed oral cancer/precancer patients 
who consent to participate in the study. 
Ghayoour Mir                           Sample oral cancers. Administer MASL. Consenting of
Subjects. Obtains hematoxylin and eosin (H&E) stained and unstained 
specimens of previously diagnosed oral cancer/precancer patients 
who consent to participate in the study. 
Eugenio Capitle
Evaluate patients before and after MASL or placebo
 
administration and manage complications should they arise.
Htay Htay Kyi                           Evaluate patients before and after MASL or placebo
 
administration and manage complications should they arise.
David Suster                     
Surgical pathologist at the UH involved with the study. Evaluate
tumor pathology, cell morphology, and PDPN expression in
 patient 
samples. 
Alan J. Shienbaum
Evaluate tumor pathology, cell morphology, and PDPN expression
Keystone Medical Labs.
in patient samples. 
Funding Source(s): ____Rowan University___________
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1.   Purpose/Specific Aims
This project will evaluate the expression of a receptor called podoplanin (PDPN) in cells from oral 
cancers and precancerous lesions. We will also determine how sensitive oral cancer cells are to 
a potential drug called Maackia amurensis seed lectin (MASL). 
1.1 Objectives
Oral cancers will be biopsied by Dr. Soly Baredes, Dr. Roden, Dr Evelyne Kalyoussef and 
Dr.Ghayoour Mir and Dr. Rabie Shanti. Precancerous oral lesions will be biopsied by Dr. Mahnaz 
Fatahzadeh. For oral cancer/precancer patients biopsied at an outside institution and referred to 
Rutgers/University Hospital for care, outside H&E slides and unstained specimens for PDPN 
staining will be requested. Dr. Suster and Dr. Alan Shienbaum will evaluate tumor pathology, cell 
morphology, and PDPN expression in these patient samples. Dr. Gary Goldberg will evaluate 
PDPN expression and MASL sensitivity from primary cultures of these cells. Study clinicians will 
evaluate oral cavity and health of their respective patients before and after MASL treatment. Dr. 
Fatahzadeh, Dr. Baredes, Dr. Kalyoussef, Dr. Shanti, Dr. Mir or Dr. Roden will administer MASL 
dosage, evaluate any effects on oral structure and epithelium, and perform clinically indicated 
resection or biopsy to obtain specimen after treatment. Dr. Fatahzadeh, Dr. Baredes, Dr. Roden, 
Dr. Shanti, Dr. Mir or Dr. Kalyoussef along with Dr. Capitle and Dr. Kyi will measure overall health 
before and after administration, and evaluate potential allergic reaction to MASL and respond to 
any unlikely scenarios. Dr. Suster, Dr. Shienbaum and Dr. Goldberg will evaluate pathology, cell 
morphology, and PDPN expression in these samples. We will determine if MASL treatment can 
decrease PDPN expression and normalize cell morphology in oral cancers and precancerous 
lesions. 
Thus, primary, secondary, and tertiary objectives are as follows:
a.
Primary Objective: To evaluate and compare the morphology and podoplanin (PDPN) 
expression of cells included in the oral lesion initial biopsy to normal oral squamous epithelial 
cells (OSCCs).
b.
Secondary Objective: To evaluate and compare the PDPN expression of cells included in the 
resected oral lesion to normal oral squamous epithelial cells.
c.
Tertiary Objective: To evaluate and compare the morphology of cells included in the resected 
oral lesion to normal oral squamous epithelial cells. 
1.2 Hypotheses
We hypothesize that the majority of oral cancers express PDPN, and that MASL inhibits the 
growth, migration, and transformed morphology of these cells. Our hypothesis predicts that more 
PDPN will be expressed in aggressive oral cancer cells (OSCCs) than normal oral epithelium 
(OSCs), and that MASL will inhibit the growth and migration of these OSCCs in a manner that 
correlates with PDPN expression in vitro, as well as normalize the morphology of these cells in 
vivo.
1.3 Primary, Secondary, and Tertiary Endpoints
Endpoints will be determined by cell morphology and PDPN expression examined by IHC. This 
work will be performed as an integral part of the study. The protocols rely on standard staining 
protocols to visual cells and PDPN expression with an approved antibody (D2-40). We have 
experience with this approach as previously described [56].   
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Our primary endpoint will be measured from patient biopsy material. We will compare the 
morphology and PDPN expression of cells included in the oral lesion to normal oral squamous 
epithelial cells. Patients eligible for the study will provide samples with lesion cells that are 
determined to be OSCC and express more PDPN than normal cells from the same sample 
specimen. In addition, these OSCC cells will express PDPN levels that are equivalent or greater 
than PDPN levels expressed by lymphatic endothelial cells (LECs) from the same specimen.  
Although this may be considered inclusion criteria, it is also an endpoint since these data will 
confirm that PDPN expression is increased in OSCC cells in our patient population. PDPN 
expression will be assessed by IHC for this endpoint since it can be used to qualitatively and 
quantitatively asses PDPN expression and be accomplished along with standard evaluations 
used for best care practice.
Our secondary endpoint will be measured from patient resection or second biopsy material. We 
will compare the PDPN expression of cells included in the oral lesion to normal oral squamous 
epithelial cells. Our secondary endpoint will be met if MASL treated OSCC cells express less 
PDPN than normal cells from the same sample specimen. In addition, these OSCC cells will 
express PDPN levels that are lower than PDPN levels expressed by lymphatic endothelial cells 
(LECs) from the same specimen. Our secondary endpoint will also require that the degree of 
PDPN expression decrease occurring after MASL administration is greater than any PDPN 
expression decrease observed after placebo administration. This comparison will be analyzed by 
t-test to achieve a p value less than 0.05.  
Our tertiary endpoint will be measured from the same patient resection or second biopsy material 
used to measure our secondary endpoint. We will compare the morphology of cells included in 
the oral lesion to normal oral squamous epithelial cells. Our tertiary endpoint will be met if MASL 
treated OSCC cells appear less dysplastic than they appeared before treatment. Dysplasia will 
be graded on a scale of 1 to 5, with 5 being the most dysplastic. Our hypothesis predicts that 
MASL treated OSCC cells will appear more cuboidal and flatter than they were before treatment.    
2.   Background and Significance
Approximately 300,000 new cases of oral cancer are diagnosed each year, causing over 120,000 
deaths worldwide [30,32]. Greater than 90% of these cancers are oral squamous cell carcinomas 
(OSCC) that proceed from hyperplasia to dysplasia, carcinoma in situ, and invasive carcinoma 
[55,27]. The potential for malignant progression of lesions including leukoplakia, erythroplakia, 
and leukoerythroplakia is primarily determined by the presence and degree of dysplasia 
[41,72,78,27].   
Patients with early (stage I or II) OSCC are generally treated with surgery and radiation therapy, 
yielding 5-year survival rates between 70% and 95% [20,12,22,11,29,50,70,36]. However, 
patients with more advanced OSCC (stage III or IV) have much lower 5 year survival rates, 
ranging between 26% and 53% [54,66,69,36]. Metastasis to cervical lymph nodes is considered 
an extremely adverse prognostic factor for patients with OSCC [85,37,36].OSCCs and 
premalignant lesions often exhibit polymorphisms in cyclin D1 and inactivation of tumor 
suppressors including p53, p16 and p14 [77,4,48,64,35,67,15,18,17,21,58,71].  Increased 
expression of tumor promoters including EGFR, c-myc, cyclin D1, TGF-α, and Pdpn are also often 
seen in such lesions [14,35,68,15,71,75,82]. Indeed, EGF signaling can induce PDPN expression 
in a number of OSCC cell lines [28]. 
PDPN expression is clearly associated with OSCC aggression, invasion, metastasis, 
postoperative recurrence, and poor survival. Taken together, reports indicate that PDPN 
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expression is notably increased in over 30% or precancerous oral lesions and in over 60% of oral 
cancers. Moreover, PDPN expression appears to correlate with oral cancer stage. About 50% of 
stage T1/T2 oral cancers display elevated PDPN expression levels, and this number increases to 
about 75% for stage T3/T4 oral cancers. In addition, over 70% of primary OSCC tumors that 
metastasize to lymph nodes express elevated PDPN levels. Clinical studies also indicate that 5 
year overall survival rates continuously decrease from 93% for patients with weak podoplanin 
expression, to 47% for patients with moderate expression, to 23% for patients with high levels of 
podoplanin expression. OSCC recurrence also correlate very well, with undetectable, weak, 
moderate, and high PDPN expression resulting in 100%, 93%, 71%, and 51% disease free 
survival rates, respectively [49,85,8,37,16,23,36,27].  
The bulk of the PDPN protein, about 150 amino acids, lies outside of the cell and could serve as 
an ideal target to combat cancer growth and progression [40,80]. For example, antibodies against 
PDPN and a PDPN interacting partner (tetraspanin CD9) can inhibit lung metastasis of CHO cells 
transfected with PDPN [34,53]. However, while antibodies may offer significant targeting 
specificity, they cannot be administered orally [3,9,31] and may not possess intrinsic 
pharmaceutical effects on melanoma cell growth and migration seen with orally available lectins. 
We have shown that Maackia amurensis seed lectin (MASL) targets PDPN to inhibit tumor cell 
growth and motility [1,38,57]. The extracellular domain of PDPN is O-glycosylated with sialic acid, 
α2,3 linked to galactose [80]. PDPN is activated by endogenous lectins that bind to these 
extracellular carbohydrate moieties [73,5,7] to induce tumor cell motility and metastasis 
[81,83,84,73]. Thus, blocking this interaction should inhibit malignant progression. For instance, 
compounds blocking the action of galectins, which activate mucin receptors, can inhibit tumor cell 
metastasis [26,19]. 
Although some lectins may nonspecifically bind to many glycoproteins, MASL can precisely target 
specific glycoproteins expressed by human cells [47,46]. We have shown that MASL, which has 
a high affinity for O-linked carbohydrate chains containing sialic acid [76,25], binds to PDPN in 
order to inhibit tumor cell growth and motility at nanomolar concentrations. As we have recently 
reported, MASL can be taken orally to inhibit tumor growth in mice. Moreover, no side effects 
were evident from MASL ingestion based on animal weight, behavior, or organ morphology. 
Lectins such as MASL offer significant medicinal value. Toxic lectins (e.g. ricin and viscumin) are 
extremely rare. In fact, lectins are found in virtually all foods [51,52]. In addition to carbohydrate 
modifications, lectin interactions are guided by amino acid residues of their target receptor proteins. 
Lectins can bind to their receptors with dissociation constants (Kd) that rival the specificity of 
kinase inhibitors (e.g. lapatinib or imatinib) [33] and antibodies used against cancer (e.g. 
trastuzumab) [10,61,6,62]. For example, C-type lectin-like receptor 2 (CLEC-2) targets PDPN with 
an average dissociation constant (Kd) of less than 4 nM [74]. In addition, unlike antibodies, lectins 
are resistant to gastrointestinal proteolysis [63,60,62] and can be taken orally to treat cancer 
[61,19,62]. Indeed, lectins can block the action of endogenous pro-metastatic lectins (such as 
galectins or selectins) to inhibit tumor cell growth [59-61], and can be used medicinally to treat 
cancer in people [62]. However, most anti-cancer lectins that have been examined thus far have 
intrinsically toxic ribosome inhibitory protein (RIP) activity similar to that of ricin, and target 
receptors that have not been identified [62]. Unlike these other lectins, MASL is not toxic to normal 
cells and targets a known receptor on cancer cells - PDPN. 
As mentioned above, antisera may offer greater targeting specificity but lectins offer the 
advantage of oral administration. Dietary legumes (lentils, peas, or beans) have been shown to 
significantly lower the incidence of skin cancer [39]. Digestion of 200 grams of peanuts results in 
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concentrations of up to 200 nM of intact peanut lectin (PNA) in circulating blood [79]. Our 
Preliminary Studies and recently published data [57] indicate that similar concentrations of our 
model leguminous lectin, MASL, survive digestion, enter the circulatory system, and can 
effectively inhibit OSCC cell growth and migration. 
Human safety for MASL has already been demonstrated as a “coincidental” component in 
traditional medicines used to treat ailments including cancer. Maackia amurensis has been used 
as a medicinal plant in Asia (called “Huai Huai” or “怀槐” in China) for several centuries 
[43,45,42,44,13]. It should also be noted that, although its targets and mechanisms are not yet 
defined, Mistletoe lectin (viscumin) binds proteins containing α2,3-sialic acid, has undergone 
clinical trials, and is widely used to treat melanoma in Europe [2,10,24]. However, human safety 
studies for MASL have not been reported.
We plan to utilize PDPN as a functionally relevant biomarker and chemotherapeutic target to 
combat oral cancer. For this project, oral cancers and precancerous lesions will be removed and 
examined for PDPN expression. Sensitivity to MASL, which targets PDPN on transformed cells, 
will be evaluated in fixed samples and primary cell cultures established from these specimens. 
MASL will then be orally administered to patients with lesions that contain cells that express PDPN 
and are sensitive to MASL. Samples from subsequent biopsies or resections, as determined by 
best care practices, will then be analyzed for PDPN expression and cell morphology. Overall oral 
and physical health will also be examined to evaluate the effects of MASL on each patient.
Thus, disease, investigation products, and rationale are as follows:
a.
Disease: oral cancer, specifically oral squamous cell carcinoma (OSCC).
b.
Investigational products: Maackia amurensis seed lectin (MASL).
c.
Rationale: MASL can be used as a nontoxic oral agent that targets the podoplanin (PDPN) 
receptor on OSCC cells topically and systemically to their growth, motility, and tumor 
progression.
3.    Research Design and Methods
This trial will conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
applicable regulatory requirements. Up to 50 patients with visible oral lesions fitting the clinical 
criteria for cancerous or precancerous lesions undergoing surgery or biopsy (as part of clinical 
care) at the NJMS or RSDM oral medicine clinic/Rutgers Dental Associates will be targeted for 
consideration as participants in this study. This includes patients with oral cancer, proliferative 
verrucous leukoplakia (PVL), conventional oral leukoplakia (OL), and erythroplakia, plus suspect 
oral papillomas and oral lichen planus. When the identified oral lesion seems appropriate, patients 
will be asked to sign an informed consent allowing a portion of the biopsy sample or excised tumor 
to be utilized for research purposes. These specimens will be transferred directly to Dr. Goldberg 
at Rowan University-SOM for preparation of cell cultures and other research-related testing. 
Oral cancers will be sampled surgically by Dr. Soly Baredes, Dr. Roden, Dr. Evelyne Kalyoussef, 
Dr. Ghayoour Mir or Dr. Rabie Shanti. Precancerous lesions will be biopsied surgically by Dr. 
Mahnaz Fatahzadeh. This work will be performed at the NJMS/RSDM/Rutgers Dental associates 
and University Hospital in Newark, NJ. Biopsy will be performed by original surgeon as 
determined by best care practice. These procedures will have been planned as a matter of course 
for the patient. Therefore, the patients’ participation in this study should not affect their treatment. 
The operating surgeon will place a sample of the tissue on wet ice. Dr. Goldberg will receive the 
tissue from the pathology department after they agree that this tissue is not needed for further 
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analysis. Dr. Goldberg will be waiting in a room as instructed by the surgeon and pathologist and 
will package the specimens on wet ice and bring them to his lab according to IATA protocols. 
Dr. Suster and Dr. Alan Shienbaum will evaluate PDPN expression and cell morphology by IHC 
from formaldehyde fixed section of these samples. Surgical specimens will be fixed in 10% 
formalin in PBS, paraffin embedded, sectioned (4 microns), and processed for hematoxylin/eosin 
staining and immunohistochemistry D2-40 monoclonal antibody (Dako) to detect PDPN as 
described [56]. Paraffin-fixed specimens will be prepared by the local oral pathology laboratories 
at the University Hospital in Newark, NJ as part of the diagnostic histopathology. Routine 
pathology reports generated during patient care will also be examined to verify the tumor grade 
and nature of these specimens. Data will be examined by Dr. Suster and Dr. Shienbaum in a 
blinded manner with coded labels such that they will not know whether the specimens are from 
MASL or placebo treated patients. 
In addition to IHC analysis, Dr. Goldberg will establish primary cell cultures from these samples. 
He will evaluate cell morphology, assay PDPN expression by Western blotting, and evaluate the 
effects of MASL on the growth and migration of these cells by standard growth and motility assays 
[57]. This work will be performed at the Science Center in Stratford, NJ. Results from these studies 
will be used to elucidate understand how OSCC cells respond to MASL. However, these cell 
culture data will not be used as eligibility criteria since these assays may not be accomplished in 
a time frame consistent with treatment plans. The IHC analysis can be completed within 4 days. 
Therefore, this testing will not delay any subsequent treatment plans or options.
Patients with OSCC cells that express robust levels of PDPN will be considered for treatment. 
Robust levels of PDPN will be defined as greater than normal cells and equivalent or greater than 
PDPN levels expressed by lymphatic endothelial cells (LECs) from the same sample specimen. 
Patients that meet the eligibility criteria will be enrolled in the treatment phase of this study. Study 
clinicians (Dr. Baredes, Dr. Roden, Dr. Kalyoussef, Dr. Shanti, Dr. Mir or Dr. Fatahzadeh) will 
administer MASL or placebo to enrolled subject. Patients will be given a lozenge (troche)with or 
without MASL added to achieve a final dosage of 100 mg per adult. Clinicians administering the 
lozenge and Dr. Goldberg are not blinded to the type of the lozenge; however, this information is 
not available to the pathologist who evaluates tumor pathology, cell morphology, and PDPN 
expression in the patient samples. 
In addition to the process described above, patients already diagnosed with oral cancer/precancer 
who present to one of the study clinicians for definitive care may also be enrolled in the study if 
they consent to participation. In these situations, it is routine to request H&E-stained slides from 
the original surgical pathology department for review as part of the surgical planning for clinical 
care. For patients who consent, the study clinician or PI would also request 1-3 unstained 
specimens for D2-40 staining to determine PDPN expression for research purposes. Patients with 
OSCC cells that express robust levels of PDPN and meet the eligibility criteria will be considered 
for treatment phase. The remainder of the protocol remains the same.
MASL and placebo lozenges will be prepared by an approved GMP certified facility by 
chromatography methods established by Dr. Goldberg as described [57]. Lozenges will be stored 
at the University Hospital Pharmacy and be hand delivered to the administering doctor by study 
investigators listed on page 1 in a sealed plastic container labeled with the patients name and ID. 
This work will be performed at the NJMS/RSDM/Rutgers Dental associates and University 
Hospital in Newark, NJ. Dr. Baredes, Dr. Kalyoussef, Dr. Roden, Dr. Shanti, Dr. Mir or Dr. 
Fatahzadeh along with Dr. Capitle and Kyi will perform a general physical evaluation of their 
respective patients before and after MASL or placebo administration. Dr. Capitle or Dr. Kyi will 
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evaluate patient vital signs including temperature, pulse, blood pressure, and overall health after 
administration. Dr. Capitle or Dr. Kyi will also assist with management of any complication should 
it arises. 
In this approach, MASL will find administration through topical exposure to oral lesions in the 
mouth as the lozenge dissolves. Patients will be asked to dissolve the lozenge in their mouth for 
at least 5 minutes before being chewed, and refrain from spitting, eating, or drinking for at least 
20 minutes after lozenge administration. Subjects will be asked to finish chewing the lozenge 
within 20 minutes. Systemic exposure through the blood stream may also be accomplished. Data 
from university studies on cell lines and animal models indicate that MASL can be applied topically 
or eaten to target PDPN in order to inhibit tumor cell growth and migration. However, 
pharmacokinetics of this compound have not been established. 
3.1. Duration of Study
This study should be completed within 24 months of the start date. Each patient will participate in 
the study for about 2 to 6 months.
3.2 Study Sites
Keystone Medical Laboratories 
781 Keystone Industrial Park
Throop, PA  18512
Science Center
Rowan University SOM
Stratford, NJ  08084
Rutgers School of Dental Medicine
Oral Medicine Clinic
110 Bergen Street
Newark, NJ  07103
Rutgers Dental Associates
90 Bergen Street (Suite 7700)
Newark, NJ   07103
Doctors Office Center
Allergy, Immunology and Rheumatology Clinic
90 Bergen Street (Suite 4500)
Newark, NJ    07103
Ambulatory Care Center 
Otolaryngology Clinic
140 Bergen Street
Newark, NJ  07103
Doctors Office Center
Otolaryngology Clinic
90 Bergen Street (Suite 8100)
Newark, NJ   07103
University Hospital (Unit 1, Pathology, OR)
150 Bergen St
Newark, NJ 07103
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3.3 Sample Size Justification
We will recruit up to 10 patients for MASL treatment and 10 patients for placebo treatment to 
attempt a p value of less than 0.05 based on a difference of 40% with respect to Podoplanin 
expression and MASL sensitivity. Patients will be selected for treatment with MASL versus 
placebo by 1:1 randomization.
 
3.4 Subject Selection and Enrollment Considerations
Subjects will be enrolled to fulfill a sample size in light of power considerations. These subjects 
will be enrolled from a well-defined population of patients presenting oral cancer or suspected 
lesions determined and treated by best care practice, and methods assuring human subjects’ 
protections, including their voluntary & informed consent, privacy of person and confidentiality of 
data, and equitable access to research.
3.5.1 Inclusion Criteria
1.)  Males and females of at least 18 years of age who are able to give consent.
2.)  Smokers and non-smokers.
3.)  Persons with white or red spots and/or lesions suspected or found to be oral cancer or 
      precancer on the inner surface of the mouth.
4.)  Oral lesions will be classified as OSCC or leukoplakia including, proliferative verrucous
      leukoplakia, conventional erythroplakia, suspect oral papillomas, or oral lichen planus. Only 
      patients with such histologically confirmed diagnoses will be considered for inclusion.
5.)  patients will be considered for inclusion at any stage of disease progression.
6.)  Patients will be considered for inclusion if a subsequent biopsy or surgical resection are
      planned as part of their best care treatment. 
7.)  Patients with previously diagnosed oral cancer/precancer who present to the study clinicians 
      for definitive surgical care, consent to participate, and meet the criteria for enrolment. 
8.)  Patients will have an Eastern Cooperative Oncology Group performance status of 0 or 1. 
9.)  Patients will display normal organ function as evidenced by standard laboratory blood tests
      including liver enzymes and creatine.
10.)  Patients will not present evidence of comorbidities including ongoing or active infection, 
      unstable illness, or medical conditions.
3.5.2 Exclusion Criteria
1.)  Patients with cognitive impairments and cannot consent for themselves.
2.)  Patients with language/hearing impairments.
3.)  Use of a topical steroid product within the last 2 weeks.
4.)  Pregnant women (to avoid any potential risk to the fetus) to be confirmed by standard blood
      or urine tests according to best care practice.
5.)  Patients who are breastfeeding.
6.)  Abstinence or use of adequate contraception will be required for women of childbearing 
      potential and men of reproductive potential.
3.5.3 Subject Recruitment
Subjects will be recruited directly by Dr. Baredes, Dr. Kalyoussef, Dr. Roden, Dr. Shanti, Dr. Mir 
and Dr. Fatahzadeh. Patients will be selected for treatment with MASL versus placebo by 1:1 
randomization.
 
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3.5.4 Consent Procedures
The consent process will take place before the initiation of the study procedures. The physicians 
will discuss this process during the first office visit prior to surgery, or earlier. Patient will be 
approached with the forms and have the protocol described to them. Participants will discuss their 
participation with the surgeons before signing the consent form. A full description of the project 
will be given to the prospective participants in lay language in sufficient time for them to consider 
whether or not to participate in the study.
The entire process will be described to each subject in lay language in order for them to fully 
understand the nature of their involvement in the research. Consent will not be sought from 
subject with cognitive and/or language/hearing impairments as described in the experimental 
protocols. 
3.5.5 Subject Costs and Compensation
There will be no costs or compensation for participants. This work will utilize samples to be taken 
during the course of standard care.
3.6 Chart Review Selection
All study documents such as consent forms, biopsy reports, and patient’s identifiers (name, 
gender, birth date, etc.) are maintained in a locked cabinet in the PI’s office (Dr. Mahnaz 
Fatahzadeh) in Newark. A copy of the relevant data (name, gender, DOB,..) including biopsy 
reports will also be kept in Dr. Gary Goldberg’s office in the science center at SOM. This 
information will not be transferred to any files used for tissue analysis or other procedures. These 
identifiers will only be accessible to cross referencing a coded sample number that is used for all 
research purposes. Patient identifiers will only be used to verify results with the physicians that 
are involved in this study. 
4.    Study Variables
4.1 Independent Variables or Interventions
4.1.1 Drug or Device Interventions
This study involves the potential drug MASL (FDA IND#: 118210). MASL will be extracted, 
purified, and compounded into lozenges by the University of California GMP facility by protocols 
that result in MASL that is essentially free of salts and other contaminants that can be successfully 
used in cell culture and animals [57,56]. Patients will be given a lozenge with or without MASL 
added to achieve a final dosage of 100 mg per adult. Patients will be given a lozenge with or 
without MASL added to achieve a final dosage of 100 mg per adult. MASL will be prepared by the 
University of California Davis GMP facility. Patients will be watched for 2 hours after administration 
and examined for any reactions to the treatment. 
As described above (see Section 3) MASL targets PDPN to inhibit tumor cell growth and motility 
[1,38,57]. Although some lectins may nonspecifically bind to many glycoproteins, MASL can 
precisely target specific glycoproteins expressed by human cells [47,46]. MASL can be taken 
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orally to inhibit tumor growth in mice. Moreover, no side effects were evident from MASL ingestion 
based on animal weight, behavior, or organ morphology [57,65]. Human safety for MASL has 
already been demonstrated as a “coincidental” component in traditional medicines used to treat 
ailments including cancer. Maackia amurensis has been used as a medicinal plant in Asia for 
several centuries, with doses averaging 100 mg per adult administration [43,45,42,44,13]. 
However, human safety studies for MASL have not been reported.
4.2 Dependent Variables or Outcome Measures
Up to 1 gram of tumor tissue will be analyzed. The cells in this tissue will be adapted to cell culture. 
Protein will be examined by IHC and Western blotting. Effects of MASL on PDPN expression, cell 
growth, migration, and morphology will be analyzed by standard growth, motility, and IHC assays. 
Patient age and sex will be correlated to these results to determine if correlations exist between 
age and sex.
4.3 Risk of Harm
Some medical risks are associated with this study since patients will be treated according to 
standard care and with an experimental nutraceutical (MASL). This compound has been used as 
an anecdotal incidental component of traditional medicines for many centuries without reports of 
harmful side effects. Risks of information distribution would involve patient name, age, sex, and 
tumor grade. These risks will be minimized by keeping information related to patient identifiers 
encoded, locked in the PI’s office, password protected, and destroyed after the study. Patient 
specimens will not be labeled with patient names or other identifiers; they will be labeled with 
unique identifiers to maintain patient privacy and confidentiality. 
Protocols are in place for assessment and treatment of potential reactions to MASL. Patients will 
be observed for 2 hours after every administration for any development of effect such as 
hypersensitivity reaction. Any individual who develops suspected allergic episode will be 
evaluated for manifestations such as urticaria, angioedema, flushing, pruritus, upper airway 
obstruction, gastrointestinal symptoms, syncope, hypotension, and lower airway obstruction. Mild 
allergic reactions will be treated with anti-histamines and/or epinephrine. If the patient has 
moderate to severe anaphylaxis, intramuscular epinephrine will be administered into the lateral 
thigh. The adult dose of 1:1,000 epinephrine is 0.2 to 0.5 mL. If there is no significant improvement 
in symptoms, then the dose will be repeated approximately every 5 to 15 minutes, as the physician 
deems to be necessary. Intravenous or oral corticosteroid 1 to 2 mg/kg per dose up to 125 mg of 
methylprednisolone will be considered to decrease the biphasic or prolonged reactions. If needed, 
oxygen up to 100% will be administered at a flow rate of 6 to 10 L/min through a facemask. 
Oxygen saturation will be monitored and kept at 94% to 96% by oximetry. For signs and symptoms 
of bronchospasm (eg, wheezing, coughing, and shortness of breath) that has not responded to 
intramuscular epinephrine, albuterol will be administered through a nebulizer and facemask. 
Hypotension will be treated with rapid fluid replacement using 1 to 2 L of 0.9% normal saline, 
infused rapidly. For the normotensive patient in anaphylaxis, starting normal saline at an 
appropriate maintenance rate for weight (125 mL/h for adults) to maintain venous access for 
medications and/or rapid fluid replacement will be considered if necessary. 
If the patient has severe anaphylaxis or is showing signs and symptoms of impending 
cardiopulmonary arrest, EMS will be summoned immediately in addition to all available office 
medical staff. Cardiopulmonary resuscitation will be started immediately in the event of 
cardiopulmonary arrest, with emphasis on adequate chest compressions without interruption. 
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Ventilations can be given once there are 2 medical staff members at the patient’s side. For 
imminent or established cardiopulmonary arrest, venous access will be rapidly established to 
administer an intravenous bolus dose of epinephrine.  For adults, the dose is 1 mg intravenously 
as a 1: 10,000 dilution that can be repeated every 3 to 5 minutes. If epinephrine is ineffective in 
treating anaphylaxis in patients taking b-blockers, then glucagon administration might be 
necessary. 
Patient’s blood pressure, cardiac rate and function, respiratory status, and oxygenation will be 
monitored and recorded at frequent and regular intervals. The duration of direct observation and 
monitoring after an episode of anaphylaxis will be individualized and based on the severity and 
duration of the anaphylactic event and response to treatment. Patients with moderate to severe 
anaphylaxis will be observed for a minimum of 4 to 8 hours. Mild anaphylactic symptoms that 
rapidly resolve with treatment usually will require a relatively shorter period of observation. At the 
time of discharge from medical supervision, patients will be instructed to call the office or call 911 
or go to the emergency room in case there is recurrence of symptoms of an allergic reaction. 
Prescription, written action plan and follow up visits deemed necessary will be discussed upon 
discharge.
4.4 Potential for Benefit
This project presents great potential for benefit. Forthcoming results should elucidate the role of 
a specific receptor in oral cancer progression, and methods to target this receptor to prevent and 
combat cancer.
5.   Data Handling and Statistical Analysis
Data will be analyzed in Excel and Prism software to evaluate means, standard errors, t-test, and 
ANOVA. Only the PI (Dr Goldberg) will have access to these raw files. Versions of these files 
without patient identifiers will be made available to the other members of this study group. Patient 
identifiers will only be used to verify results with the physicians that are involved in this study. 
Records with identifiers will be destroyed 6 years after completion of the study. This time is 
needed to complete laboratory experiments on the collected samples and allows tracing and re-
examination of the histological slides should any question regarding diagnosis arises.  
6.   Data and Safety Monitoring
The effects of MASL on overall patient health and oral health will be monitored by trained 
physicians and dentists before and after each dose. No other drugs or devices will be given to 
patients. Attending investigators will evaluate adverse effects in real time. Data will be collected 
and stored with security measures used to protect it from loss or inappropriate use by password 
protection, restricted access, and, database backup. 
An independent safety monitoring group has been set up for this study. The name of the Data 
Safety Monitoring Board (DSMB) is “MASL data safety monitoring board”. The group will meet 
bimonthly, and will generate a written report from each meeting. These meetings will be closed to 
the public, and the group will be supplied with records and descriptions of patient responses in 
the study and scientific data that is obtained from the study. These descriptions will be complete, 
but the study coordinator will remove patient names and any personal identifiers before they are 
given to the group for evaluation. The group will use these descriptions to generate reports that 
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will contain 3 sections divided into: (1) Assessment of progress, (2) Presentation and analysis of 
any problems that arise, and (3) Recommendations based on assessment of progress and 
problems. Examples of problems that arise may include reactions of patients to the study drug 
including rashes, changes in heart rate, temperature, or breathing. Written reports will be available 
to the IRB since the director of the DSMB will send them directly to the study coordinator who will 
upload them to the Study Profile on the eIRB website. The group will be made up of the following 
professionals which include basic scientists (PhD) and a physician (MD, PhD) with experience in 
molecular and cell biology, acute reactions and shock, nutrition and digestion, and biostatistics:
Name and degrees
 Position
 Affiliation
 Expertise
Kingsley Yin, Ph.D
 Assistant 
Professor
 Rowan-SOM
Molecular and cell biology, 
physiology, acute reactions and 
shock (Dr. Yin will serve as DSMB 
director)
Raymond Birge, Ph.D.
Professor
Rutgers-NJMS
Signal transduction, tumor cell 
survival and migration, 
chemotherapy mechanisms
 Robert Steer, Ph.D.
  Professor
 Rowan-SOM
Basid and clinical research  analysis 
and biostatistics
Peter Stein, Ph.D.
 Professor
 Rowan-SOM
Nutrition, digestion, effect of 
compounds on disease including 
diabetes, Alzheimer’s, and autism, 
and research ombudsman
7.   Reporting Results
      7.1 Individual Results
Participants will not receive results since they are relevant to basic science and molecular events 
that underlie fundamental aspects of OSCC cell growth, migration, and tumorigenesis.
       7.2 Aggregate Results
Participants will not receive results since they are relevant to basic science and molecular events 
that underlie fundamental aspects of OSCC cell growth, migration, and tumorigenesis.
        7.3 Professional Reporting
Data will be collected and analyzed in a blind manner. Results will be published in peer reviewed 
journals to share results of this research with the scientific community. 
Study Design Flowchart
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Biopsy
High PDPN
Expression
Low PDPN
Expression
High PDPN
Expression
Low PDPN
Expression
Resection
Best Care
Resection
Best Care
Normalized PDPN
Expression &
Cell Morphology
No Effect on PDPN
Expression &
Cell Morphology
Hypothesis
Supported
Hypothesis
Refuted
IHC
NJMS
MASL
Treatment
No MASL
Treatment
IHC
NJMS
RSDM
IHC
NJMS
Biopsies taken from patients will be examined by immunohistochemistry (IHC). Patients with 
lesions with high PDPN expression who meet the eligibility criteria for the trial phase will be offered 
MASL treatment before resection or second biopsy as determined by best care practice. Surgical 
specimens will then be examined by IHC to examine the effects of MASL on PDPN expression 
and cell morphology. Our hypothesis predicts that MASL will reduce PDPN expression and 
normalize the morphology of oral squamous carcinoma cells. 
NJMS
RSDM
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Schedule of Events
Subject Recruitment
Identification of patients with premalignant or malignant lesions during the course of clinical care 
(this includes previously diagnosed oral cancer/precancer patients presenting for surgical 
resection as part of clinical care)
informed consent 
Dr. Fatahzadeh
Dr. Baredes        
Dr. Roden
Dr. Kalyoussef  
Dr. Shanti 
Dr. Mir  
Clinical procedures as per best care practice
Diagnostic tissue biopsy
Dr. Fatahzadeh
Dr. Baredes        
Dr. Roden
Dr. Kalyoussef  
Dr. Shanti   
Dr. Mir
Laboratory Procedures
Diagnostic histopathology, Evaluation of cell morphology & PDPN expression
Identification of patient samples with robust PDPN expression
Dr. David Suster 
Dr. Alan Sheinbaum
Clinical procedures as per best care practice
Planning resection or second biopsy 
Dr. Fatahzadeh
Dr. Baredes         
Dr. Kalyoussef   
Dr. Roden
Dr. Shanti
Dr. Mir
Treatment Phase
Evaluation of eligibility criteria for enrolment. Eligible patients:

Have tissue samples with robust PDPN expression 

Have not used topical steroid products within the last 2 weeks

Have Eastern Cooperative Oncology Group performance status of 0 or 1. 

Display normal organ function as evidenced by standard laboratory blood tests including liver 
enzymes and creatine.

Do not present evidence of comorbidities including ongoing or active infection, unstable illness, 
or medical conditions.

Not pregnant as per standard blood or urine tests according to best care practice

Not breast feeding

Consent to Abstinence or use of adequate contraception (women of childbearing potential and 
men of reproductive potential)
Dr. Fatahzadeh
Dr. Baredes
Dr. Kalyoussef
Dr. Roden
Dr. Shanti
Dr. Mir
MASL administration within 1 week of planned biopsy or resection
Dr. Fatahzadeh
Dr. Baredes          
Dr. Kalyoussef   
Dr. Capitle 
Dr. Kyi         
Dr. Roden
Dr. Shanti
Dr. Mir
Clinical procedures as per best care practice
Planned resection or second biopsy
Dr. Fatahzadeh  
Dr. Baredes
Dr. Kalyoussef
Dr. Roden
Dr. Shanti
Dr. Mir
Laboratory Procedures
Diagnostic histopathology, Evaluation of cell morphology & PDPN expression
Dr. David Suster
Dr. Alan Sheinbaum
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