







































Evaluating the Efficacy of Targeted 
Inhibitor Therapeutics for Sonic 

Hedgehog Medulloblastoma: 
Significant Milestones and Current 

Limitations
 Maria Victoria Dias, Bridgitte Isom, Katherine Poole, Sofia 

Triplett, Nadia Sadanandan

Volume One 
Edition One 
February 2021  

 
GEORGETOWN SCIENTIFIC
RESEARCH JOURNAL

84



Georgetown Scientific Research Journal  

https://doi.org/10.48091/ATJH8708  

 

Evaluating the Efficacy of Targeted Inhibitor 
Therapeutics for Sonic Hedgehog 
Medulloblastoma: Significant Milestones and 
Current Limitations 

Maria Victoria Dias, Bridgitte Isom, Katherine Poole, Sofia Triplett and 
Nadia Sadanandan 

School of Nursing and Health Studies, Georgetown University, Washington 
DC, United States 
 
E-mail: nas146@georgetown.edu, md1694@georgetown.edu, 
krp60@georgetown.edu, sft9@georgetown.edu, bei5@georgetown.edu 
 
Abstract 
Medulloblastoma (MB) is the most common pediatric brain tumor with the Sonic Hedgehog (SHH) 
subtype accounting for 30% of all diagnoses. The current standard treatment regimen includes high doses 
of toxic chemotherapy and radiation, as well as surgical resection, motivating the need for alternative 
therapies which do not generate deleterious effects on patients. The purpose of this literature review was 
to evaluate the most recent developments in the efficacy of targeted therapeutics in treatment of SHH 
MB, specifically focusing on small molecule inhibitors targeting the Sonic Hedgehog pathway. The 
sources analyzed in this review include case studies, preclinical and clinical studies, and other review papers 
that investigate the mechanism and value of five SHH inhibitors: vismodegib, sonidegib, glasdegib, 
temozolomide, and GANT-61. Novel discoveries have highlighted that inhibitor therapeutics effectively 
target aberrant activity of the SHH pathway at various stages, thereby diminishing tumor progression and 
metastasis. Through evaluation of the inhibitors, it was determined that they are promising targeted 
therapeutics for SHH MB, despite their limitations. These limitations include drug resistance, molecular 
heterogeneity of SHH-driven tumors, and poor drug properties. More research will be needed to 
overcome these obstacles for clinical use, but the investment is warranted given the promise of these 
inhibitors. Future research should seek to establish optimal dosage and timing of intervention, further 
delineate the genetic basis for SHH MB, and investigate potential combination therapies with SHH 
inhibitors.  
Keywords: Medulloblastoma, Sonic Hedgehog Pathway, Inhibitor Therapeutics, Vismodegib, Sonidegib, 
Glasdegib, Temozolomide, GANT-61, Pediatric, Cancer, SHH, Sonic Hedgehog, SMO, PTCH

  

85



Georgetown Scientific Research Journal 

https://doi.org/10.48091/ATJH8708 

1. Introduction

Medulloblastoma (MB) is a malignant brain
tumor first described by Harvey Cushing and 
Percival Bailey in their classification of central 
nervous system (CNS) tumors in 1925.  Although 
it is the most common pediatric malignant brain 
tumor, representing about 20% of all pediatric 
brain tumors,1 it is very rare in adults, representing 
0.4 to 1% of adult brain tumors.2 Most cases are 
diagnosed under age 16 and it is rarely seen after 
age 40. In the United States, an average of 500 
children and 200 adults are diagnosed with MB 
every year, and it is more common in males than 
females.3 Medulloblastoma is part of the primitive 
neuroectodermal tumors (PNET) group, which is 
classified within the embryonal subtype of CNS 
tumors. It originates in the cerebellum, in the 
posterior fossa, and may spread to other regions of 
the brain and spinal cord. The World Health 
Organization classified medulloblastoma into four 
non-histological subgroups according to molecular 
profiling of the tumors: Wingless (WNT), Sonic 
Hedgehog (SHH), and groups 3 and 4. This 
review will focus on the SHH subtype because it 
accounts for 30% of all MB diagnoses and is the 
most prominent subtype in both infants (< 3 years 
of age) and adults (> 17 years of age).4 

       First introduced in the 1930s, surgery was the 
initial treatment approach. However, the mortality 
rate following the operation exceeded 30%.5 In 
1953, craniospinal irradiation was introduced 
following surgery, and although there was 
improvement to a 3-year survival rate of 65%, the 
development of significant motor and cognitive 
side effects was observed. Non-specific cytotoxic 
chemotherapy complemented with surgery and/or 
radiation was then introduced in the 1970s, and it 
is still the standard treatment today. 
Unfortunately, the unforeseen long-term use of 
this high toxicity treatment therapy has caused 
extensive toxic damage to patients, particularly in 
younger patients.6 Cerebellar mutism, dysarthria, 
and neurocognitive disorders result in over 25% of 
patients following treatment, as well as the growth 

of secondary tumors due to high intensity of 
radiation and chemotherapy. Moreover, the 
current standardized treatment fails to address the 
root cause of tumor growth, and along with the 
occurrence of serious adverse effects, validates the 
need for non-toxic, individualized therapy which 
tackles the substantial variability of pathological 
mechanisms among the four subtypes. 
       Currently, a substantial amount of research is 
focused on developing targeted therapeutics for 
SHH MB in order to meet this need. Since the 
overactivation of the SHH pathway may play a 
critical role in the formation of this MB subtype, 
creating therapeutics that can mitigate aberrations 
to the SHH pathway serves as a putative treatment 
strategy. Evidence indicates that SHH signaling 
directs developmental processes, such as cell 
differentiation and morphogenesis, and has been 
implicated in several cancers.7  Importantly, proper 
SHH signaling is crucial for neural tube formation 
and normal cerebellar development, as the pathway 
mediates the proliferation of cerebellar granule 
cells (GCs) during embryonic development. The 
heightened activation of the SHH pathway leads 
to the overproliferation of cerebellar GCs, which 
may culminate in tumorigenesis.8 This pathway 
shows the most promise for developing effective 
inhibitors, as shown by the extensive amount of 
research that has been dedicated to understanding 
its mechanism and the role of SHH signaling in 
generating medulloblastoma. 
       The purpose of this literature review is to 
evaluate the most notable recent developments in 
targeted inhibitor therapeutics as a possible 
treatment for SHH MB and suggest further 
research that would improve the efficacy of the 
inhibitors. The sources examined describe the 
mechanism of action and value of five SHH 
inhibitors: vismodegib, sonidegib, glasdegib, 
temozolomide, and GANT-61. Significant work 
has been recently devoted to the development of 
these inhibitors, and researchers need to 
understand the extent of this recent progress in 
order to plan their next steps. Therefore, this 
review serves as an important resource because it 

86



Georgetown Scientific Research Journal 

https://doi.org/10.48091/ATJH8708 

presents a summary and evaluation of findings 
regarding the efficacy of SHH inhibitors, as well 
as potential future steps to eventually use these 
therapeutics in clinical practice. Overall, novel 
findings suggest that inhibitors of the SHH 
pathway exhibit efficacy in suppressing the 
pathway and diminishing tumor growth in SHH 
MB; however, further investigation is needed to 
overcome the limitations that arise with these 
therapeutics. 

2. The Hedgehog Pathway

SHH-MB is named as such because the
overactivation of the SHH pathway is the 
mechanism driving the formation of this tumor. 
Evidence suggests that mutations in genes that 
contribute to the SHH pathway may generate 
tumorigenesis. Some of these genes include the 
patched homologue 1 gene (PTCH1), 
smoothened homologue gene (SMO), and the 
suppressor of fused homologue gene (SUFU). 
Heightened expression of the GLI zinc finger 
transcription factors (GLI1, GLI2, GLI3) and 
MYCN, an oncogene, has also been associated 
with the formation of SHH MB. When the ligand 
for the SHH pathway is not present, the Patched 
1 (PTCH) protein, a 12 transmembrane receptor 
protein, represses the smoothened receptor 
(SMO), thereby inhibiting the pathway. As shown 
in Figure 1, when a PTCH ligand, such as sonic 
hedgehog, is present, it binds to PTCH1 and 
activates the pathway, as SMO is no longer 
suppressed. Next, SMO is moved to the primary 
cilium, and it then activates a GLI zinc finger 
transcription factor, which could be GLI1, GLI2, 
or GLI3. Once a GLI factor is stimulated, the 
transcription of target genes for the SHH pathway 
(e.g. GLI1, PTCHI1, cyclin D1, BCL-2, SNAIL) 
is promoted. Anomalous activity at any stage of 
this pathway may spur the formation of 
medulloblastoma. The most prominent drivers of 
SHH MB include aberrant expression of SHH 
target genes, PTCH dysfunction, and SMO 
promotion.6  To counter the deleterious effects of 

these SHH pathway permutations, targeted small 
molecule inhibitors that prevent the SHH ligand 
from binding to PTCH or antagonists of SMO 
have risen as potential therapeutics against SHH 
MB. 

Figure 1. An overview of the hedgehog signaling 
pathway. In the absence of a PTCH ligand (e.g. 
sonic hedgehog), PTCH represses SMO. Once 
sonic hedgehog binds, PTCH no longer inhibits 
SMO, and SMO is translocated to the primary 
cilium, where it subsequently activates GLI 
transcription factors that promote target gene 
expression of the hedgehog pathway.  
3. Mechanism of Action for Small Molecule
Inhibitors of The Sonic Hedgehog Pathway
The following SHH pathway inhibitors are 
potential targeted therapeutics for SHH MB: 
vismodegib, sonidegib, glasdegib, temozolomide, 
and GANT-61. As seen in Figure 2, they target 
and block specific parts of the hedgehog pathway. 
They are not yet approved for treatment for MB.  

�#!/,�5h8�$POUJOVFE�PO�OFYU�QBHF��

87



Georgetown Scientific Research Journal 

https://doi.org/10.48091/ATJH8708 

Figure 2. Overview of where the inhibitors target 
the pathway. As shown, vismodegib targets 
PTCH1 and SMO. Glasdegib and sonidegib are 
SMO antagonists. GANT-61 is a GLI inhibitor. 

       However, both vismodegib and sonidegib 
were approved for metastatic non-resectable Basal 
Cell Carcinoma in 2012 and 2015, respectively. 
Glasdegib was approved in 2018 for acute 
leukemia treatment.6 

        Vismodegib is a small molecule drug taken 
orally. In regard to the SHH pathway described 
above, it interacts with SMO and PTCH by 
specifically blocking activities of hedgehog-ligand 
cell surface receptors PTCH and/or SMO. By 
blocking the process here, hedgehog signaling is 
suppressed. When vismodegib (also known as 
GDC-0449) blocks PTCH, SMO can continue to 
be repressed, and not further the cycle.9 

Vismodegib acts as an SMO antagonist, blocking 
the SMO receptor. This prevents SMO from 
activating the GLI zinc finger transcription 
factors, further inhibiting the pathway. 
Vismodegib is also a kinase inhibitor, meaning 
that it inhibits activity of the enzyme kinase 
(kinases can add phosphate groups to proteins and 
change their functions). In an in vivo study, 
vismodegib has been shown to affect complete 
tumor regression in mice with doses of 12.5 mg/kg 
administered twice per day.10,11 Additionally, 
vismodegib has been shown to yield vast but 
impermanent tumor regression and relief of 
symptoms when given orally with a dose of 540 
mg/day for 3 months. This data is important in 
evaluating the efficacy of targeted inhibitors to the 
SHH pathway as therapeutics for SHH MB. 

       Sonidegib is also a SMO antagonist. 
Sonidegib works by penetrating the blood-brain 
barrier and blocking the SMO receptor and 

therefore the SHH pathway, making it a 
potentially effective treatment for SHH MB. It 
has inhibited tumor growth in mice when 
administered at 5 mg/kg/day and is shown to allow 
for more regression at higher doses. However, 
these are also transient effects, and after being 
exposed to sonidegib for a long time, it has been 
shown that resistance/relapse occurs due to 
mutations in SMO that are formed. Moreover, 
while preclinical research has demonstrated 
momentary efficacy of sonidegib in SHH MB, the 
beneficial effects dwindle over time due to SMO 
mutations and serve as a significant limitation.12 

Additionally, glasdegib is a SMO antagonist. It 
functions due to its benzimidazole scaffold which 
has been shown to be used as an anticancer agent.13 
It has a very high potency, indicating that it may 
effectively inhibit tumor growth in SHH MB. As 
mentioned before, it has been FDA approved 
along with low doses of cytarabine for treating 
acute leukemia.14,15 

In addition to preclinical research, clinical trials 
have evaluated the efficacy of sonidegib and 
vismodegib at mitigating MB tumor growth, as 
well as their safety profile. 16-21 In a phase I trial 
conducted from 2007 to 2008, vismodegib was 
administered to 68 patients who had refractory, 
locally advanced, or metastatic solid tumors caused 
by aberrant hedgehog pathway signaling.         
One of these patients had SHH MB. The SHH 
MB patient demonstrated a partial but 
unconfirmed response to increasing doses of 
vismodegib, as well as an acceptable safety profile. 
Resistance to vismodegib occured in this patient as 
a result of SMO mutations, revealing vismodegib’s 
potential as a therapy for SHH MB while 
highlighting mutations as a drawback. This clinical 
trial is not recent, however. Much more research 
has been conducted on vismodegib’s efficacy in 
SHH MB patients since 2008, producing 
conclusions that are more revealing.17 A more 
recent clinical trial regarding vismodegib was 
conducted in 2013.  Vismodegib was provided to 6 
patients at a dose of 85 mg/m2, and 7 patients 
received a 170mg/m2 dose. There was no bone 

88



Georgetown Scientific Research Journal 

https://doi.org/10.48091/ATJH8708 

toxicity documented from the drug, although 
dose-limiting toxicities did manifest. This study 
served to evaluate the safety, the toxicity, and 
efficacy of vismodegib in pediatric patients with 
recurrent or refractory MB. Ultimately, the study 
showed that this SMO inhibitor is safe and feasible 
in children, which is significant considering the 
lack of pediatric clinical trials with SMO 
inhibitors. A subsequent study administered a 
phase II dosage to three out of seven SHH MB 
patients from the first phase. Notably, antitumor 
activity was observed in 1 of these patients.18 These 
clinical findings suggest vismodegib’s robust safety 
and efficacy in SHH MB patients.  
       In 2 phase II studies conducted in 2015, 31 
adult patients and 12 pediatric patients  were 
treated with 150-300 mg/d of vismodegib. 
Responses were evaluated with neuroimaging and 
molecular tests. Protocol defined response outlined 
that a complete or partial response must be 
sustained for 8 weeks. A complete response was 
achieved when all lesions targeted disappeared, 
and a partial response was achieved when 30% 
reduction in the sum of the diameter of long 
lesions targeted. 3 adult patients and 1 pediatric 
patient  with SHH-MB achieved the protocol-
defined response. Progression-free survival was 
longer for patients with SHH-MB than non-
SHH-MB. Prolonged disease stabilization was 
achieved in 41% of patients with SHH-MB. It was 
concluded that vismodegib acts against adult 
recurrent SHH-MB and not non-SHH-MB. For 
pediatric patients, there was no conclusion. It was 
also concluded that SMO inhibitors depend on the 
deviations in the genome of the tumor.19 Taken 
together, vismodegib seems to work by specifically 
targeting the SHH pathway, which explains its 
inefficacy against non-SHH-MB tumors. While 
this clinical data is promising, vismodegib needs to 
be studied much more extensively in pediatric 
patients and its efficacy in mitigating mutated 
SHH MB tumors needs to be explored.  
       In a similar manner to vismodegib, sonidegib 
has also been clinically assessed as an inhibitor of 
the SHH pathway in MB patients.20, 21 In 2014, a 

phase I clinical trial was conducted to assess the 
safety and efficacy of sonidegib taken orally in 
patients with MB and basal cell carcinoma (BCC). 
The prominent dose-limiting toxicity manifested 
as a 3/4 increase in creatine kinase in blood serum, 
which developed in 18% of patients. Nonetheless, 
sonidegib displayed  an adequate safety profile and 
decreased expression of GLI1 mRNA in a dose-
dependent manner.20 Therefore, this clinical 
evidence suggests sonidegib’s safety and efficacy in 
curtailing MB tumor growth by inhibiting 
progression of the SHH pathway. In a 2017 phase 
II trial, 60 pediatric patients and 16 adult patients 
with recurrent tumors received oral sonidegib 
treatment. Pediatric patients received a 680mg/m2 
daily dose, while adults received 800mg. Out of all 
the pediatric patients, 39 had MB. A 5-gene Hh 
signature assay was conducted to determine the 
genetic driver of tumors in complete responders, 
partial responders, and non responders to 
sonidegib treatment. Notably, it was found that 
among the complete responders, 2 children and 2 
adults, had SHH-driven tumors. This same 
outcome was found in the one partial responder.        
       Out of the 50 non-responders, none 
demonstrated an SHH-driven tumor.21 This is 
significant because it indicates that sondigeib 
shows efficacy in mitigating MB tumor growth, 
specifically by inhibiting the SHH pathway. 
Overall, these clinical trials indicate that while 
both vismodegib and sonidegib show substantial 
promise as SHH inhibitors in MB, several 
limitations to their efficacy still need to be 
overcome. Thus, the clinical investigation of other 
potential SHH inhibitors is also warranted.   
Temozolomide - another SHH small molecule 
inhibitor - is not yet approved, but there are 
ongoing studies about its use as a monotherapy or 
in combination with vismodegib. It functions by 
preventing DNA duplication in cells during 
proliferation, causing cell death.22 Therefore, 
temozolomide works to disrupt division of tumor 
cells and consequently, hinders tumor growth. 
Though SHH MB seems amenable to 
temozolomide’s mechanism of action, the most 

89



Georgetown Scientific Research Journal 

https://doi.org/10.48091/ATJH8708 

effective dosage has not yet been established. For 
instance, vismodegib and temozolomide 
monotherapies were studied in a patient with 
recurrent SHH MB, and were taken at a dose of 
150 mg. The patient responded to both 
vismodegib and temozolomide over a significant 
period of time, though the efficacy of both 
treatments eventually waned due to drug 
resistance. Several mutations occurred to SMO: 
SMO-L412P, SMO-G477L, and PIK3CA-
H1065L mutations, which indicates the 
importance of a treatment regimen that targets 
multiple aspects of the SHH pathway. 
Determining the optimal dosage of these SHH 
inhibitors in preclinical studies is critical before 
moving to clinical trials, where patient safety is at 
risk. Additionally, since the benefits of the 
pharmaceutics seem to dwindle over time, 
delineating time of intervention over the course of 
the disease progression is also essential to better 
treating patients.23

       Lastly, GANT-61 is a GLI inhibitor. 
Inhibiting GLI in the SHH pathway may be an 
effective anti-cancer therapeutic. It has been 
studied in Daoy cells, a medulloblastoma cell line. 
The study found that GANT-61 succeeded at 
inhibiting GLI, a key transcription factor in the 
SHH pathway, downregulated the Bcl-2 target 
genes, and even made the tumor cells more 
sensitive to cisplatin (a chemotherapy drug).24 This 
yielded a significant inhibition of cell proliferation, 
which would theoretically inhibit tumor growth in 
vivo. 
4. Evaluation: Therapeutic Potency of SHH
Inhibitors in SHH-MB
       Targeted small molecule inhibitors of the 
SHH pathway have proven to be a promising 
therapeutic for SHH MB. Many studies and 
reviews indicate that these inhibitors are effective 
at halting proliferation.24, 25 Overall, there are three 
main benefits of these inhibitors that contribute to 
their efficacy: their capacity to directly target the 

SHH pathway, their infrequent toxicities, and 
their intimate connection with the SHH pathway 
genes. However, significant limitations exist. 
Resistant mutations and the heterogeneity of the 
disease are two major limitations, and poor drug 
properties is a minor (but important) limitation. 
This section will address these benefits and 
limitations. 
4.1 Precision Yet Resistance 
       Novel investigations evaluating the efficacy of 
targeted inhibitor therapeutics in SHH MB have 
demonstrated the capacity of these inhibitors to 
bind specifically to various factors in the SHH 
pathway, thereby preventing its progression. This 
makes targeted inhibitors an effective therapeutic 
because it attacks the cancer at the heart of its 
mechanism for proliferation. Poisoning the cells 
that carry the mechanism through chemotherapy, 
an alternative treatment, is not as precise. 
Sonidegib illustrates this. MB growth in mice 
decreased by 33% more than the control group 
following sonidegib treatment.25 By targeting the 
SMO protein, sonidegib prevented SMO’s 
translocation to the primary cilium, thereby 
halting the pathway. As a result, tumor progression 
significantly declined at a dose dependent rate, 
indicating its potential for treating SHH MB.25 

Another example is a 2016 study examining the 
efficacy of GANT-61, a GLI transcription factor 
inhibitor in SHH MB. The overexpression of this 
gene is associated with several cancers. In the 
study, varied concentrations of GANT-61 were 
administered to Doay cells, which serves as the in 
vitro model of MB. By inhibiting GLI, GANT-
61 promoted apoptosis of the Daoy cells and 
downregulated the Bcl-2 target gene, substantially 
inhibiting cell proliferation.24 Both GLI and Bcl-2 
are components of the SHH pathway, illuminating 
how these inhibitors attack the MB cancer at the 
site of tumor initiation. In summary, the examples 
of sonidegib and GANT-61 illustrate that SHH 
targeted inhibitors are effective because they target 
the MB cancer at its source: the SHH pathway. 

90



Georgetown Scientific Research Journal 

https://doi.org/10.48091/ATJH8708 

       Although the targeting nature of small 
molecule inhibitors is a significant benefit, 
mutations in the SHH pathway genes often lead to 
resistance. These mutations create proteins in the 
SHH pathway that interfere with the inhibitors’ 
effects, rendering them ineffective at halting tumor 
growth. For example, multiple sources reveal that 
SMO point mutations result in proteins that do 
not allow for inhibitor binding.1,6 Overall, patterns 
in current literature indicate that SMO, SUFU, 
GLI2, and MYCN are the genes that primarily 
experience inappropriate amplifications or 
mutations resulting in resistant effects. Patterns in 
these mutations and how each mutation results in 
resistance is still unclear, but multiple studies 
report that SUFU, GLI2, and MYCN are all 
downstream from SMO.1, 19, 26 For example, one 
clinical trial found that patients with the 
downstream genes did not respond to SMO 
antagonists at all or initially responded to the 
antagonists but later experienced recurrence.26 
Conversely, this clinical trial and a separate clinical 
trial found that SHH MB patients with mutations 
in the upstream PTCH1 gene did respond to the 
inhibitors.19, 26 These variable clinical responses are 
due to the heterogeneity of the disease and 
mutations that lead to resistance.23, 26 Furthermore, 
a pattern in clinical trials has emerged where SHH 
MB patients’ tumors will initially shrink, only to 
be followed with recurrent growth.6, 26, 27 These 
patterns are supported by in vitro experimentation. 
Inhibitors such as sonidegib and novel Artemisinin 
derivatives significantly halted MB proliferation 
during early stages of experimentation but were 
unable to overcome resistant mutations that led to 
recurrent proliferation.12, 28-30 It should be noted 
that not all of the sources agree on which gene 
mutations result in resistance. Most sources 
comment on SUFU, GLI2, and MYCN, but one 
review also discusses truncations of GLI1, 
amplifications of GLI2, cyclin D1, and 
upregulation of the ATP binding cassette 
transporter p-glycoprotein substrate. Given that 
the other sources did not mention these mutations, 
it is unclear whether they pose a significant 

limitation. Overall, resistant mutations pose a 
serious limitation to the efficacy of the inhibitors 
because they undo the exact mechanism used to 
halt proliferation of the MB cells. More research is 
needed to clarify which mutations most contribute 
to resistance and how they do so. However, the 
following additional benefits of SHH inhibitors 
still make these therapeutics a promising option.  
4.2 Less Toxic Yet Less Stable 
       Notable advancements have revealed that 
targeted inhibitor therapeutics of SHH MB are 
much less invasive and toxic than the current 
standardized treatment. A 2010 investigation 
demonstrated that SHH inhibitors are an effective 
mode of treatment for other SHH-dependent 
cancers, such as Basal Cellular Carcinoma, Lung 
cancer, and Liver cancer.31  Since 2015, SHH 
inhibitors have been a validated treatment option, 
specifically for treating metastatic or locally 
advanced non-resectable Basal Cellular 
Carcinoma.25 Therefore, SHH inhibitors 
demonstrate rehabilitative potential in SHH MB, 
which is driven by aberrations in the SHH 
pathway. Administration of SHH inhibitors have 
been shown as safe with limited adverse effects, as 
indicated by its clinical approval for Basal Cell 
Carcinoma. Moreover, these inhibitors’ low 
toxicity and limited invasiveness suggest its greater 
therapeutic capacity in comparison with current 
standardized treatment. For example, vismodegib 
and temozolomide have exhibited a promising 
safety index in recent investigations. One 
vismodegib clinical trial found that the patients 
revealed a low toxicity profile and that none of the 
patients withdrew from the clinical trial because of 
toxicity.19 Another clinical trial found that a 16-
year old patient suffering from SHH MB 
exhibited a steady response to vismodegib and 
temozolomide with limited adverse effects. 
Although the benefits eventually declined due to 
mutations, this study demonstrates that adverse 
events were not due to toxicity. 23 Nonetheless, 
surgical resection and subsequent radiation and 

91



Georgetown Scientific Research Journal 

https://doi.org/10.48091/ATJH8708 

chemotherapy are still the most prevalent 
treatment regimen for all MB subtypes. Given that 
the invasive nature of radiation and chemotherapy 
often generate chronic cytotoxic effects and tumor 
recurrence, inhibitors are a promising alternative.  
       Although this data indicates that inhibitors 
improve upon the standard treatment regimen for 
SHH MB in terms of toxicity and invasiveness, 
evidence suggests that developing inhibitors 
without these cytotoxic effects and optimal 
pharmacokinetic properties has posed a challenge. 
For example, two SHH pathway inhibitors that 
resulted in negative consequences are cyclopamine 
and HhAntag: cyclopamine generated cytotoxic 
effects in healthy cells and a preclinical study of 
HhAntag resulted in permanent developmental 
defects in the bones of the mouse models.32, 33 

Given that SHH is a pathway critical for 
development, the latter study has raised concerns 
about the use of SHH inhibitors in infants and 
young children. Cyclopamine also had poor 
pharmacokinetic properties, another limitation of 
SHH MB inhibitors. Adequate concentration and 
stability in circulation are two pharmacokinetic 
properties that have been commented on in the 
literature. For example, rat livers cleared away N-
Phenylbenzamide too quickly, preventing 
adequate concentration. This ended its testing 
although it was initially promising.34 Other 
examples are GANT-61 and vismodegib. GANT-
61 has proven effective in vitro but is less stable 
than its GANT-58 alternative under physiological 
conditions.35 Vismodegib has demonstrated 
encouraging pharmacokinetic characteristics in 
animal models, but its pharmacokinetic properties 
can also be improved upon. An in vivo study 
demonstrated that these properties can be further 
bolstered when hydrogen ions in the active sites are 
replaced with deuterium. This allowed for 
sustained benefits at lower doses.36 Overall, 
although poor drug properties are important 
limitations, literature suggests that they are not as 
significant as genetic based limitations such as 
resistant mutations and heterogeneity. Most of the 
sources analyzed did not comment extensively on 

the cytotoxicity and pharmacokinetic properties, if 
at all. These challenges should be addressed, 
however, as the development of novel SHH 
inhibitors progresses.  
4.3 Genetic Connections Yet Persistent Heterogeneity 
       Recent developments in the use of SHH 
inhibitors have also elucidated connections 
between the genetics of the disease and the efficacy 
of inhibitors. These connections have allowed 
researchers to craft treatment regimens that target 
specific genetic mutations, bolstering their 
efficacy. In 2015, a clinical study reported results 
from two Phase II trials that evaluated the safety 
and efficacy of vismodegib in patients with 
recurrent or refractory SHH MB.19 It was found 
that the position of the genomic deviation in 
relation to SMO and PTCH1 were predictors of 
the response to SMO inhibitor activity. Both the 
transgressions of SMO and PTCH1 culminated in 
favorable outcomes with respect to attenuating 
tumor progression. This discovery is critical 
because it demonstrates that knowing the genetic 
basis of the patients’ SHH MB tumor can predict 
whether or not they respond favorably to the 
inhibitor. Secondly, it was discovered that robust 
P53 diffuse staining in SHH MB was associated 
with a substantially less significant response to the 
inhibition of SMO. The mechanism underlying 
this finding is not yet understood because the 
relationship between P53 and SMO is unclear. 
However, results indicated that mutations of this 
protein generate chromothripsis, where thousands 
of chromosomal rearrangements occur, possibly 
upregulating the expression of SHH signaling 
oncogenes.37 With this information, paired with 
the relationship between P53 and SMO that still 
requires further investigation, it is concluded that 
alterations to the P53 protein expression may be 
correlated with anomalous SMO activity.19   
       Moreover, inhibitors that can mitigate both 
P53 and SMO aberrancy, which are driven by 
genetic mutations, serve as a potential therapeutic 
strategy for SHH MB. This underscores the 

92



Georgetown Scientific Research Journal 

https://doi.org/10.48091/ATJH8708 

relationship between SHH MB’s genetics and 
efficacy of inhibitors. A third key finding from this 
study was the delineation of the target population 
for vismodegib therapy, which was conducted via 
complete molecular profiling of SHH MBs. The 
evidence obtained demonstrated the importance of 
distinguishing SHH MBs that are driven by 
mutations downstream in the SHH pathway, 
which are not amenable to the inhibition of SMO. 
This serves as a significant milestone because it 
suggests the need for novel inhibitor therapeutics 
that target different proteins of the pathway while 
underscoring that inhibitor efficacy has genetic 
connections. This emphasizes the importance of 
further delineating the genetic basis of SHH MB 
in order to provide more effective individualized 
therapies.  
       Although there are useful connections 
between inhibitor efficacy and disease genetics, not 
all of the SHH MB genes have been discovered 
and important patterns in expression have yet to be 
identified. Much of the literature describes SHH 
MB as a heterogeneous disease, meaning that 
different genes are associated with tumor growth 
across patients. There is evidence for this in the 
variability of responses to inhibitors. For example, 
two adult males suffering from SHH MB had 
extremely different responses to vismodegib. One 
had a very favorable response while the other 
developed resistance multiple times. Furthermore, 
the second adult male even had a genetic profiling 
more similar to the childhood version of the 
disease, making it difficult to predict how he would 
respond to the treatment.27 This highlights the 
complexity of the disease’s genetic basis and 
suggests that there are subgroups of SHH MB 
based on combinations of affected genes. 
However, these nuances are still unclear because it 
is a rare cancer; more patients are required to detect 
patterns with certainty. This makes it difficult for 
researchers to develop effective inhibitors and 
assign patients to optimal clinical trials.6 

Furthermore, some genes might even be better 
suited for use as a diagnostic tool while other genes 
(such as GLI) have shown promising results as a 

therapeutic target.24 Overall, the heterogeneity of 
SHH MB limits the efficacy of inhibitors in that 
they might not target the pathway optimally in 
each patient. Fortunately, studies have successfully 
identified preliminary patterns of tumor-inducing 
gene expression in SHH MB patients using 
transcriptome sequencing and whole genome 
analysis. These studies have found that there are 
patterns across age groups.1,26 One study found that 
infants, children, and adults had instances of 
PTCH1 mutations, only infants had the SUFU 
mutations, and only adults had SMO mutations. 
Mutations in SUFU, GLI2, and MYCN genes 
have shown primary resistance to SMO 
inhibition.26 This suggests that patients in clinical 
trials should be assigned inhibitors according to 
age, and that genetic sequencing of SHH MBs 
should be a part of the treatment planning process. 
Ultimately, a better understanding of the 
responsible genes is still needed.  
       Overall, the potential of SHH inhibitors 
makes them a promising therapeutic for SHH MB 
in the clinical setting, despite their limitations. 
Future research must address these limitations if 
the inhibitors are to be approved for clinical use. 
However, the promise of these inhibitors warrants 
the investment of such research. Given how they 
have improved upon the standard treatment 
regimen for SHH MB, small molecule inhibitors 
of the SHH pathway are likely the future of SHH 
MB treatment. 

93



Georgetown Scientific Research Journal  

https://doi.org/10.48091/ATJH8708  
 

 

 
5. Further Research Needed 
         The current limitations of SHH inhibitors in 
SHH MB illuminate crucial areas of future 
research. First, optimal dosage and timing of 
intervention need to be established. In a case study, 
vismodegib and temozolomide were taken at a 
dose of 150mg. The therapeutic benefits of both 
inhibitors dwindled as mutations arose. The new 
tumors that formed varied genetically from the 
initial tumor. Following failure of those 
treatments, sonidegib was taken at a dose of 
400mg, which resulted in the need for emergency 
surgery.23 Therefore, optimizing dosage and timing 
of intervention are crucial for translating 
preclinical findings to clinical practice. 
Importantly, optimal timing and dosage of 
inhibitor treatment should be examined for both 
pediatric and adult patients, especially since 
clinical trials with pediatric SHH MB subjects are 
lacking. 

         Compared to the standard treatment regimen 
for SHH MB (radiation, chemotherapy, and 
surgery), SHH inhibitors demonstrate greater 
therapeutic promise. Nevertheless, future research 
should focus on improving the efficacy of these 
inhibitor therapeutics to combat resistant 
mutations. Resistance to both SMO antagonists 
and inhibitors of PTCH frequently develop in 
patients, which can exacerbate tumor growth and 
spur other adverse events. Moreover, more 
downstream inhibitors of the SHH pathway, such 
as GLI inhibitors, should be explored in studies. 
Investigation into various SHH inhibitors is also 
critical for treatment of SHH MB in pediatric 
patients, as SHH MB in the pediatric setting most 
often occurs due to genetic mutations downstream 
of SMO in the pathway.26 It is also important to 
consider the use of combination inhibitor therapies 
for SHH MB. Since the efficacy of SHH 
inhibitors, such as vismodegib, may diminish over 
time due to drug resistance, synergistic inhibitor 
treatment with other therapies may elicit a more 
robust rehabilitative response. It may be beneficial 
to target both the SHH pathway and other 
pathways that interact with SHH signaling, such 
as P53, cAMP, Atoh1, Boc, CxCl12, CxCR4, and 
PI3K.1,19 For example, though the interaction 
between P53 and the SHH pathway remains 
unclear, an in vivo study found that development 
of MB increased from 14% to more than 95% 
when PTCH loss was coupled with P53 loss.38 
Moreover, administration of SHH inhibitors with 
P53 mediators should be explored as a putative 
combination therapy for SHH MB. Additionally, 
cholesterol homeostasis may contribute to the 
overactivation of the SHH pathway and so, 
modulated inhibitor therapies that can also 
obstruct cholesterol regulation may serve as an 
important area of future research. Indeed, a recent 
milestone investigation not only demonstrated 
that lipid-based nanoparticles effectively crossed 
the blood brain barrier and delivered the 
therapeutic cargo to the tumor site, but also 
effluxed cholesterol from the cytosol of tumor 
cells.39 Lower levels of cytoplasmic cholesterol 

94



Georgetown Scientific Research Journal  

https://doi.org/10.48091/ATJH8708  
 

 

generated cytotoxic effects in the SHH MB cells. 
Moreover, the use of lipid-based nanoparticles to 
carry targeted inhibitor therapeutics may bolster 
the efficacy of these pharmaceuticals and reduce 
the drug dosage needed to elicit a response.   
         Lastly, the pathological mechanisms of SHH 
MB are still largely unknown due to substantial 
molecular heterogeneity in these tumors. There are 
still a multitude of genes that drive this tumor that 
have not yet been identified, making it difficult to 
determine which inhibitor therapeutic would be 
most effective.6 Among infants, children, and adult 
patients, the genetic basis of the tumor differs 
significantly. Future investigations should focus on 
further elucidating the genetic basis of SHH MB 
tumors to determine whether there is an age-
dependent factor underlying the molecular 
disparities. Therefore, individualized targeted 
treatment aiming to alleviate the specific 
aberration in the SHH pathway is critical for 
formulating the most effective treatment of SHH 
MB in both pediatric and adult patients. All in all, 
extensive genetic profiling of SHH MB tumors 
serves as a pivotal area of future research. 
6. Summary 
         In summary, in understanding the SHH 
pathway and inhibitors vismodegib, sonidegib, 
glasdegib, temozolomide, and GANT-61, benefits 
as well as limitations were exposed. Drug 
resistance due to SMO mutations, molecular 
heterogeneity, and poor drug properties were 
discussed. Gaps in knowledge for future research 
include establishing a more thorough 
understanding of the genetic basis of the disease, 
determining optimal dosage of the inhibitors, as 
well as time of intervention, pathological 
mechanisms, and synergistic treatments to 
improve efficacy. In conclusion, targeted inhibitors 
of the SHH pathway are a promising treatment 
method, though there are limitations that must be 
further explored to improve the efficacy and safety 
as a therapeutic treatment for Sonic Hedgehog 
Medulloblastoma. 

Acknowledgements 
         We acknowledge the NHS and Dr. Tilan.  
References 
1. Huang, S. Y., & Yang, J. Y. (2015). Targeting 

the hedgehog pathway in pediatric 
medulloblastoma. Cancers, 7(4), 2110-2123. 
https://doi.org/10.3390/cancers7040880 

2. Majd, N., & Penas-Prado, M. (2019). Updates 
on management of adult 
medulloblastoma. Current treatment options in 
oncology, 20(8), 1-24. 
https://doi.org/10.1007/s11864-019-0663-0 

3. The University of Texas MD Anderson 
Cancer Center. Medulloblastoma. 
https://www.mdanderson.org/cancer-
types/medulloblastoma.html. 

4. Northcott, P. A., Buchhalter, I., Morrissy, A. 
S., Hovestadt, V., Weischenfeldt, J., 
Ehrenberger, T., ... & Lichter, P. (2017). The 
whole-genome landscape of medulloblastoma 
subtypes. Nature, 547(7663), 311-317. 
https://doi.org/10.1038/nature22973 

5. Millard, N. E., & De Braganca, K. C. (2016). 
Medulloblastoma. Journal of child 
neurology, 31(12), 1341-1353. 
https://doi.org/0.1177/0883073815600866 

6. Liu, X., Ding, C., Tan, W., & Zhang, A. 
(2020). Medulloblastoma: Molecular 
understanding, treatment evolution, and new 
developments. Pharmacology & 
therapeutics, 210, 107516. 
https://doi.org/10.1016/j.pharmthera. 
2020.107516 

. Sari, I. N., Phi, L. T. H., Jun, N., Wijaya, Y. 
T., Lee, S., & Kwon, H. Y. (2018). Hedgehog 
signaling in cancer: a prospective therapeutic 
target for eradicating cancer stem 
cells. Cells, 7(11), 208. https://doi. 
org/10.3390/cells7110208 

. Shimada, I. S., Hwang, S. H., Somatilaka, B. 
N., Wang, X., Skowron, P., Kim, J., ... & 
Mukhopadhyay, S. (2018). Basal Suppression 
of the Sonic Hedgehog Pathway by the G-

95



Georgetown Scientific Research Journal  

https://doi.org/10.48091/ATJH8708  
 

 

protein-coupled-receptor Gpr161 restricts 
medulloblastoma pathogenesis. Cell reports, 
22(5), 1169-1184. 
https://doi.org/10.1016/j.celrep.2018.01.018 

. National Center for Biotechnology 
Information (2021). PubChem Compound 
Summary for CID 24776445, Vismodegib. 
Retrieved February 4, 2021 
from https://pubchem.ncbi.nlm.nih.gov/comp
ound/Vismodegib. 

1 . Dlugosz, A., Agrawal, S., & Kirkpatrick, P. 
(2012). Vismodegib. Nature reviews Drug 
discovery, 11(6), 437. 
https://doi.org/10.1038/nrd3753. 

11. Gould, S. E., Low, J. A., Marsters Jr, J. C., 
Robarge, K., Rubin, L. L., de Sauvage, F. J., ... 
& Yauch, R. L. (2014). Discovery and 
preclinical development of vismodegib. Expert 
opinion on drug discovery, 9(8), 969-984. 
https://doi.org/10.1517/17460441.2014.92081
6 

12. Atwood, S. X., Sarin, K. Y., Whitson, R. J., 
Li, J. R., Kim, G., Rezaee, M., ... & Tang, J. 
Y. (2015). Smoothened variants explain the 
majority of drug resistance in basal cell 
carcinoma. Cancer cell, 27(3), 342-353. 
https://doi.org/10.1016/j.ccell.2015.02.002 

13. Munchhof, M. J., Li, Q., Shavnya, A., 
Borzillo, G. V., Boyden, T. L., Jones, C. S., ... 
& Tkalcevic, G. T. (2012). Discovery of PF-
04449913, a potent and orally bioavailable 
inhibitor of smoothened. ACS medicinal 
chemistry letters, 3(2), 106-111. 
https://doi.org/10.1021/ml2002423 

14. Fukushima, N., Minami, Y., Kakiuchi, S., 
Kuwatsuka, Y., Hayakawa, F., Jamieson, C., ... 
& Naoe, T. (2016). Small!molecule Hedgehog 
inhibitor attenuates the leukemia!initiation 
potential of acute myeloid leukemia 
cells. Cancer science, 107(10), 1422-1429. 
https://doi.org/10.1111/cas.13019 

15. Wolska-Washer, A., & Robak, T. (2019). 
Glasdegib in the treatment of acute myeloid 
leukemia. Future Oncology, 15(28), 3219-3232. 
https://doi.org/10.2217/fon-2019-0171 

16. Li, Y., Song, Q., & Day, B. W. (2019). Phase 
I and phase II sonidegib and vismodegib 
clinical trials for the treatment of paediatric 
and adult MB patients: a systemic review and 
meta-analysis. Acta neuropathologica 
communications, 7(1), 1-8. 
https://doi.org/10.1186/s40478-019-0773-8 

1 . LoRusso, P. M., Rudin, C. M., Reddy, J. C., 
Tibes, R., Weiss, G. J., Borad, M. J., ... & 
Von Hoff, D. D. (2011). Phase I trial of 
hedgehog pathway inhibitor vismodegib 
(GDC-0449) in patients with refractory, 
locally advanced or metastatic solid 
tumors. Clinical cancer research, 17(8), 2502-
2511. https://doi.org/10.1158/1078-
0432.CCR-10-2745.  

1 . Gajjar, A., Stewart, C. F., Ellison, D. W., 
Kaste, S., Kun, L. E., Packer, R. J., ... & 
Curran, T. (2013). Phase I study of 
vismodegib in children with recurrent or 
refractory medulloblastoma: a pediatric brain 
tumor consortium study. Clinical Cancer 
Research, 19(22), 6305-6312. 
https://doi.org/10.1158/1078-0432.CCR-13-
1425. 

1 . Robinson, G. W., Orr, B. A., Wu, G., 
Gururangan, S., Lin, T., Qaddoumi, I., ... & 
Gajjar, A. (2015). Vismodegib exerts targeted 
efficacy against recurrent sonic hedgehog–
subgroup medulloblastoma: results from phase 
II pediatric brain tumor consortium studies 
PBTC-025B and PBTC-032. Journal of 
Clinical Oncology, 33(24), 
2646.https://doi.org/10.1200/JCO.2014.60.15
91. 

2 . Rodon, J., Tawbi, H. A., Thomas, A. L., 
Stoller, R. G., Turtschi, C. P., Baselga, J., ... 
& Mita, A. C. (2014). A phase I, multicenter, 
open-label, first-in-human, dose-escalation 
study of the oral smoothened inhibitor 
Sonidegib (LDE225) in patients with 
advanced solid tumors. Clinical cancer 
research, 20(7), 1900-1909. 
https://doi.org/10.1158/1078-0432.CCR-13-
1710.  

96



Georgetown Scientific Research Journal  

https://doi.org/10.48091/ATJH8708  
 

 

21. Kieran, M. W., Chisholm, J., Casanova, M., 
Brandes, A. A., Aerts, I., Bouffet, E., ... & 
Geoerger, B. (2017). Phase I study of oral 
sonidegib (LDE225) in pediatric brain and 
solid tumors and a phase II study in children 
and adults with relapsed 
medulloblastoma. Neuro-oncology, 19(11), 
1542-1552. 
https://doi.org/10.1093/neuonc/nox109. 

22. Wang, C., Wu, H., Evron, T., Vardy, E., 
Han, G. W., Huang, X. P., ... & Stevens, R. 
C. (2014). Structural basis for Smoothened 
receptor modulation and chemoresistance to 
anticancer drugs. Nature communications, 5(1), 
1-11. https://doi.org/10.1038/ncomms5355. 

23. Petrirena, G. J., Masliah-Planchon, J., Sala, 
Q., Pourroy, B., Frappaz, D., Tabouret, E., ... 
& Padovani, L. (2018). Recurrent extraneural 
sonic hedgehog medulloblastoma exhibiting 
sustained response to vismodegib and 
temozolomide monotherapies and inter-
metastatic molecular heterogeneity at 
progression. Oncotarget, 9(11), 10175. 
https://doi.org/10.18632/oncotarget.23699. 

24. Lin, Z., Li, S., Sheng, H., Cai, M., Ma, L. Y. 
S., Hu, L., ... & Zhang, N. (2016). 
Suppression of GLI sensitizes 
medulloblastoma cells to mitochondria-
mediated apoptosis. Journal of cancer research 
and clinical oncology, 142(12), 2469-2478. 
https://doi.org/10.1007/s00432-016-2241-1. 

25. Pan, S., Wu, X., Jiang, J., Gao, W., Wan, Y., 
Cheng, D., ... & Dorsch, M. (2010). 
Discovery of NVP-LDE225, a potent and 
selective smoothened antagonist. ACS 
medicinal chemistry letters, 1(3), 130-134. 
https://doi.org/10.1021/ml1000307. 

26. Kool, M., Jones, D. T., Jäger, N., Northcott, 
P. A., Pugh, T. J., Hovestadt, V., ... & Pfister, 
S. M. (2014). Genome sequencing of SHH 
medulloblastoma predicts genotype-related 
response to smoothened inhibition. Cancer 
cell, 25(3), 393-405. 
https://doi.org/10.1016/j.ccr.2014.02.004. 

2 . Lou, E., Nelson, A. C., & Kool, M. (2019). 
Differential response of SHH-expressing adult 
medulloblastomas to the sonic hedgehog 
inhibitor vismodegib: whole-genome 
analysis. Cancer biology & therapy, 20(11), 
1398-1402. 
https://doi.org/10.1080/15384047.2019.16470
57. 

2 . Casey, D., Demko, S., Shord, S., Zhao, H., 
Chen, H., He, K., ... & Pazdur, R. (2017). 
FDA approval summary: sonidegib for locally 
advanced basal cell carcinoma. Clinical Cancer 
Research, 23(10), 2377-2381. 
https://doi.org/10.1158/1078-0432.CCR-16-
2051. 

2 . Danial, C., Sarin, K. Y., Oro, A. E., & Chang, 
A. L. S. (2016). An investigator-initiated 
open-label trial of sonidegib in advanced basal 
cell carcinoma patients resistant to 
vismodegib. Clinical Cancer Research, 22(6), 
1325-1329. https://doi.org/10.1158/1078-
0432.CCR-15-1588. 

3 . Liu, G., Xue, D., Yang, J., Wang, J., Liu, X., 
Huang, W., ... & Zhang, A. (2016). Design, 
synthesis, and pharmacological evaluation of 
2-(2, 5-dimethyl-5, 6, 7, 8-
tetrahydroquinolin-8-yl)-N-aryl propanamides 
as novel smoothened (Smo) 
antagonists. Journal of medicinal 
chemistry, 59(24), 11050-11068. 
https://doi.org/10.1021/acs.jmedchem.6b0124
7. 

31. Peukert, S., & Miller!Moslin, K. (2010). 
Small!molecule inhibitors of the hedgehog 
signaling pathway as cancer 
therapeutics. ChemMedChem: Chemistry 
Enabling Drug Discovery, 5(4), 500-512. 
https://doi.org/ 10.1002/cmdc.201000011 

32. Iovine, V., Mori, M., Calcaterra, A., 
Berardozzi, S., & Botta, B. (2016). One 
hundred faces of cyclopamine. Current 
pharmaceutical design, 22(12), 1658-1681. 
https://doi.org/ 
10.2174/1381612822666160112130157. 

97



Georgetown Scientific Research Journal  

https://doi.org/10.48091/ATJH8708  
 

 

33. Kimura, H., Ng, J. M., & Curran, T. (2008). 
Transient inhibition of the Hedgehog pathway 
in young mice causes permanent defects in 
bone structure. Cancer cell, 13(3), 249-260. 
https://doi.org/10.1016/j.ccr.2008.01.027. 

34. Romer, J. T., Kimura, H., Magdaleno, S., 
Sasai, K., Fuller, C., Baines, H., ... & Curran, 
T. (2004). Suppression of the Shh pathway 
using a small molecule inhibitor eliminates 
medulloblastoma in Ptc1+/! p53!/! 
mice. Cancer cell, 6(3), 229-240. 
https://doi.org/10.1016/j.ccr.2004.08.019. 

35. Agyeman, A., Jha, B. K., Mazumdar, T., & 
Houghton, J. A. (2014). Mode and specificity 
of binding of the small molecule GANT61 to 
GLI determines inhibition of GLI-DNA 
binding. Oncotarget, 5(12), 4492. 
https://doi.org/10.18632/oncotarget.2046 

36. Wang, F., Jiang, H., Deng, Y., Yu, J., Zhan, 
M., Zhao, L., & Chen, Y. (2018). Design, 
synthesis and biological evaluation of 
deuterated Vismodegib for improving 
pharmacokinetic properties. Bioorganic & 
medicinal chemistry letters, 28(14), 2399-2402. 
https://doi.org/10.1016/j.bmcl.2018.06.025. 

3 . Forment, J. V., Kaidi, A., & Jackson, S. P. 
(2012). Chromothripsis and cancer: causes and 
consequences of chromosome 
shattering. Nature Reviews Cancer, 12(10), 
663-670. https://doi.org/10.1038/nrc3352. 

3 . Wetmore, C., Eberhart, D. E., & Curran, T. 
(2001). Loss of p53 but not ARF accelerates 
medulloblastoma in mice heterozygous for 
patched. Cancer research, 61(2), 513-516. 

3 . Kim, J., Dey, A., Malhotra, A., Liu, J., Ahn, 
S. I., Sei, Y. J., ... & Kim, Y. (2020). 
Engineered biomimetic nanoparticle for dual 
targeting of the cancer stem-like cell 
population in sonic hedgehog 
medulloblastoma. Proceedings of the National 
Academy of Sciences, 117(39), 24205-24212. 
https://doi.org/10.1073/pnas.1911229117 

98




	Biological and Physical Interactions at Local Ocean Scales: Coupled Systems
	Determinants of Hepatocellular Carcinoma in the United States: Differences in Risk Factor and Geneti
	The Preventative and Healing Properties of Performing Arts in Female Genital Mutilation 
	Policy Brief: Comparison and Recommendations for State COVID-19 Responses of New Mexico and Utah
	Interplay of Nicotine and Social Stress Mediate Dopaminergic Neuron Firing in the Ventral Tegmental 
	Evaluating the Efficacy of Targeted Inhibitor Therapeutics for Sonic Hedgehog Medulloblastoma: Signi
	Refractory Epilepsy: Mechanisms of Pharmacoresistance 
	Table of Contents

