Innovation -OLD

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[av_heading heading=’Topics to Explore’ tag=’h1′ link=” link_target=” style=’blockquote modern-quote’ size=” subheading_active=” subheading_size=” margin=” padding=’10’ icon_padding=’10’ color=’custom-color-heading’ custom_font=’#043c59′ icon_color=” show_icon=” icon=’ue800′ font=” icon_size=” custom_class=” id=” admin_preview_bg=” av-desktop-hide=” av-medium-hide=” av-small-hide=” av-mini-hide=” av-medium-font-size-title=” av-small-font-size-title=” av-mini-font-size-title=” av-medium-font-size=” av-small-font-size=” av-mini-font-size=” av-medium-font-size-1=” av-small-font-size-1=” av-mini-font-size-1=”][/av_heading]

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[av_font_icon icon=’ue883′ font=’entypo-fontello’ style=” caption=” size=’30px’ position=’left’  color=” link=” linktarget=” animation=” id=” custom_class=” av_uid=’av-2bfpyy’ admin_preview_bg=”][/av_font_icon] Our Science

[av_font_icon icon=’ue883′ font=’entypo-fontello’ style=” caption=” size=’30px’ position=’left’  color=” link=” linktarget=” animation=” id=” custom_class=” av_uid=’av-2bfpyy’ admin_preview_bg=”][/av_font_icon]MLL-rearranged ALL & AML

[av_font_icon icon=’ue883′ font=’entypo-fontello’ style=” caption=” size=’30px’ position=’left’  color=” link=” linktarget=” animation=” id=” custom_class=” av_uid=’av-2bfpyy’ admin_preview_bg=”][/av_font_icon]Chromosomal Abnormalities and the Onset of Cancer

[av_font_icon icon=’ue883′ font=’entypo-fontello’ style=” caption=” size=’30px’ position=’left’  color=” link=” linktarget=” animation=” id=” custom_class=” av_uid=’av-2bfpyy’ admin_preview_bg=”][/av_font_icon]Recurrent Chromosomal Anomalies in ALL and AML

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Biomea Fusion is creating a new generation of small molecule inhibitors that target genetically defined diseases with high unmet need. These diseases all have biomarker-identifiable patient populations that will be targeted via in silico designed small molecules with new mechanisms of actions that likely become best in class. The in silico and preclinical work is designed to produce an optimized product profile of high potency with a benign safety profile (“Clean Drugs”). We believe that the product profile (best in class potent and clean), and genetically defined disease drivers putatively reduce the technical risk of each project. The novel MOA for unmet clinical programs will create scarcity value to the therapeutic assets that, if successfully developed, will have significant clinical and financial value.

More specifically, Biomea has created a potential first-in-class irreversible Menin inhibitor that blocks the protein-protein interaction between Menin and the MLL complex, a traditionally difficult target and interaction to drug. Menin associates with MLL, a protein which undergoes a gene alteration in acute leukemias (AML and ALL) and is an essential mediator for oncogenic target gene deregulation caused by a large variety of different KMT2A (=MLL) fusion proteins. In addition, Menin and the Menin-MLL complex is a required activator of other downstream leukemic driver mutations (such as NPM1) and many solid and liquid tumors are dependent on Menin for survival and propagation. By effectively inhibiting Menin, Biomea believes that patients with MLL fusions and NPM1 mutations will see significant clinical benefit.

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Biomea Fusion inhibiting Menin

Fig. 1 Transcriptional upregulation of leukemic drivers: HOX genes, MEIS1, EZH2, …

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[av_heading heading=’MLL-rearranged ALL and AML’ tag=’h1′ link=” link_target=” style=’blockquote modern-quote’ size=” subheading_active=” subheading_size=” margin=” padding=’10’ icon_padding=’10’ color=’custom-color-heading’ custom_font=’#043c59′ icon_color=” show_icon=” icon=’ue800′ font=” icon_size=” custom_class=” id=” admin_preview_bg=” av-desktop-hide=” av-medium-hide=” av-small-hide=” av-mini-hide=” av-medium-font-size-title=” av-small-font-size-title=” av-mini-font-size-title=” av-medium-font-size=” av-small-font-size=” av-mini-font-size=” av-medium-font-size-1=” av-small-font-size-1=” av-mini-font-size-1=”][/av_heading]

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Two Clinically Challenging Leukemias in Desperate Need of Alternative Treatment Options

In the USA alone, every year about 6,000 patients are diagnosed with and about 1,500 succumb to a blood cancer commonly known as Acute Lymphoblastic Leukemia (ALL). In addition, a much higher number of patients are confronted with a closely related, but even more aggressive form of leukemia: Acute Myeloid Leukemia (AML), with an annual incidence of over 21,000 patients is responsible for almost 11,000 annual deaths (2019, SEER).

European numbers are similar and, as also applies to the USA, these numbers are steadily rising due to an aging population, a partially related general rise in cancer incidence, and the projected slow but steady increase of ALL and AML-inducing treatment schemes based on anti-topoisomerase II inhibitors such as, for instance, doxorubicin or mitoxantrone for a variety of other primary tumors.

Considered together ALL and AML are amongst the most frequently occurring leukemias, both in (very) young children as well as in adults, and despite some steady but unfortunately rather limited progress in treatment outcomes, both leukemias still reflect a very grim prognosis as is reflected by the numbers above.

For ALL, the median age at diagnosis is only 15 years with 57.2% of patients diagnosed at younger than 20 years of age. In contrast, only 26.8% of cases are diagnosed at 45 years or older and only approximately 11% of patients are diagnosed at 65 years or older. ALL represents 75% to 80% of acute leukemias among children, making it the most common form of childhood leukemia; by contrast, ALL represents approx. 20% of all leukemias among adults (source: NCCN Guidelines version 2.2016 for Acute Lymphoblastic Leukemia).

AML, on the other hand, is the most common form of acute Leukemia among adults and, as such, accounts for the largest number of annual deaths from leukemias in the United States. In contrast to ALL, which is a disease that is clearly more prevalent among the young, the median age of diagnosis of AML is 67 years, with 54% of patients diagnosed at 65 years or older (and approximately a third diagnosed at >75 years of age). Thus, as the population ages, the incidence of AML seems to be rising (source: NCCN Guidelines version 1.2017 for Acute Myeloid Leukemia).

MLL protein (Mixed Lineage Leukemia) plays a critical role in epigenetic regulation of cell replication and survival through its interaction with Menin. Menin, considered a master regulator in gene expression, represents a novel target for small molecule development against the above-mentioned deadly forms of leukemia. MLL-r Leukemia (leukemias with KMT2A / MLL1 gene rearrangement), is considered the most aggressive subset of leukemia and is found in approximately 10-15% of all leukemias. MLL-r Leukemia represents a significant unmet need with an annual incidence of approx. 7,000 in the United States alone.  These patients are currently treated with standard treatment of age-adjusted induction of Ara-C, a chemotherapy, which has shown to have little impact versus non-MLL patients (see figure 2 below).

MLL

Fig. 2 Kaplan-Meier estimates of event-free survival for ALL patients with rearranged or germline MLL (Behm et al)

The development of precision medicine against fusion-driven tumors, as in the case of MLL-r Leukemias, represents Breakthrough-Therapy potential due to the importance of the pathway involved and the subsequent impact from a targeted agent.  Due to the high level of translational readthrough of the pre-clinical data to the clinical trial outcomes, the development timeline from IND filed to FDA approval has been shown to be extensively shortened (From ~8.5 years to 4.5 years).

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[av_heading heading=’Chromosomal Abnormalities and the Onset of Cancer: A Causal Relationship’ tag=’h1′ link=” link_target=” style=’blockquote modern-quote’ size=” subheading_active=” subheading_size=” margin=” padding=’10’ icon_padding=’10’ color=’custom-color-heading’ custom_font=’#043c59′ icon_color=” show_icon=” icon=’ue800′ font=” icon_size=” custom_class=” id=” admin_preview_bg=” av-desktop-hide=” av-medium-hide=” av-small-hide=” av-mini-hide=” av-medium-font-size-title=” av-small-font-size-title=” av-mini-font-size-title=” av-medium-font-size=” av-small-font-size=” av-mini-font-size=” av-medium-font-size-1=” av-small-font-size-1=” av-mini-font-size-1=”][/av_heading]

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It has been known for quite some time, that certain cancers contain specific chromosomal defects that are believed to be causally related to the onset and/or progression of the disease. An early example of such a chromosomal anomaly is the so-called Philadelphia (Ph’) chromosome, which was first identified in 1959 by Drs. Hungerford and Nowell (both working in Philadelphia at the time, hence the name), and which is the result of a balanced chromosomal translocation where the tips of chromosomes 9 and 22 break off, and swap places, as is illustrated in the scheme below:

Philadelphia Chromosone

Fig.3 Schematic of the Philadelphia chromosome formation
(https://en.wikipedia.org/wiki/Philadelphia_chromosome)

As was first discovered by Janet Rowley’s group in Chicago (in 1973), by juxtaposing the ABL1 gene on chromosome 9 to the BCR (breakpoint cluster region) gene on chromosome 22, a fusion gene residing on the aberrant chromosome 22 (or: Ph’ chromosome) is formed, which encodes an abnormal Bcr-abl protein that is responsible for causing the disease (in this particular case mainly a form of blood cancer called Chronic Myeloid Leukemia).

The normal Bcr protein functions as a growth “switch” (a so-called tyrosine kinase) that can be switched on or off, depending on the normal physiological needs of the cell, but the abnormal Bcr-abl protein, which in principle has retained this same function, lacks the off-switch, and is therefore constitutively “on”, thereby spurring cancer growth.

When detailed knowledge regarding the above biological mechanism and, consequently, a novel obvious drug target became available, several companies initiated programs aiming at disrupting the aberrant growth signal triggered by the Bcr-abl protein. In the late 1990s, Novartis developed a drug (imatinib mesylate, marketed in the USA as Gleevec), that was able to rather specifically bind to the active site within the Bcr and Bcr-abl protein and, by doing so, shut off the protein, and take away the main growth stimulus for the cancer cells. Indeed, the development of Gleevec has greatly improved overall survival rates in Ph’-positive CML.

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[av_heading heading=’Recurrent Chromosomal Anomalies in ALL and AML’ tag=’h1′ link=” link_target=” style=’blockquote modern-quote’ size=” subheading_active=” subheading_size=” margin=” padding=’10’ icon_padding=’10’ color=’custom-color-heading’ custom_font=’#043c59′ icon_color=” show_icon=” icon=’ue800′ font=” icon_size=” custom_class=” id=” admin_preview_bg=” av-desktop-hide=” av-medium-hide=” av-small-hide=” av-mini-hide=” av-medium-font-size-title=” av-small-font-size-title=” av-mini-font-size-title=” av-medium-font-size=” av-small-font-size=” av-mini-font-size=” av-medium-font-size-1=” av-small-font-size-1=” av-mini-font-size-1=”][/av_heading]

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Interestingly, about 15% (estimates vary between 5% and 20%) of ALL and AML cases are found to contain a similar, but distinctly different chromosomal anomaly. In this case it frequently involves the KMTA2 (or: MLL1, which is an old synonym for KMT2A) gene which resides on the long arm of chromosome 11 and encodes Lysine [K]-specific Methyl Transferase 2A, an enzyme with a role in the epi-genetic regulation of DNA activation and one of many (over 80 have been described) fusion genes (discussed below). It should also be noted that leukemias with MLL1 involvement seem to be most resistant to existing therapy and have a relatively grim prognosis.

Interestingly, in infant leukemias, MLL1 rearrangements occur at an incidence as high as 70-80%

The scenario involved here is strikingly similar: chromosomal changes typically trigger the break of MLL1 (here referred to as KMT2A) within the breakpoint cluster region (indicated with “BCR” in Figure 4 below).

KMT2A ProteinFig. 4 Functional domains within the normal KMT2A protein.

  • MBD: Menin-binding domain
  • AT: “AT hooks” -> these bind to AT-rich DNA in a rather a-specific manner
  • SNL: Speckled nuclear localization signals -> these target the protein to the nucleus
  • RD: repression domain (the CXXC domain contained herein is depicted in black)
  • BCR: Breakpoint Cluster Region -> this is where the large majority of oncogenic gene fusions occur
  • PHD: PhD fingers -> involved in chromatin-mediated gene regulation
  • BD: Bromodomain -> recognizes acetylated lysine residues (“histone reader domain”)
  • CS1/CS2: Taspase 1 proteolytic cleavage sites
  • FYRN / FYRC: interaction domains of Taspase 1 generated MLL-N and MLL-C fragments
  • TAD: Transactivation domain (i.e. the enzymatic domain of the protein)
  • SET: H3K4 histone methyltransferase domain (i.e. the enzymatic domain of the protein)

Two reciprocal fusion genes are formed, one of which contains the MLL1 protein domains that reside upstream (or: N-terminal) of the breakpoint cluster region, followed by none or more functional domains encoded by the C-terminus of one of the fusion genes, (in the below graph, AF4 is listed as an example) as shown in Figure 5 below.

Fusion Partner (e.g., AF4)Fig. 5 Schematic representation of typical, oncogenic KMT2A (= MLL1) fusion proteins.


Fig. 6 Proteins involved in repressive functions of MLL are grouped above, whereas proteins involved in activation
of MLL-dependent transcription are grouped below the schematic KMT2A bar.

The expected reciprocal fusion product (composed of the N-terminal of one of the fusion genes fused to the C-terminus of KMT2A) appears be formed in only a minority of KMT2A-rearranged patients (less than 15%), and is therefore considered to only play a minor role (if one at all) in the tumorigenic process. In addition, experiments with these reciprocal fusion genes / proteins have shown that these are typically not able to trigger tumor formation like the fusion gene that contains the MBD, AT, SNL and RD domains of KMT2A / MLL1 (like the one shown in figure 6 above) is able to do.

Hence, the fusion protein schematically shown in figure 6 is generally believed to drive tumor initiation and/or progression, and should therefore be considered a rational target for drug development efforts, comparable to the Bcr-abl protein described above.

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The Histone–lysine N-methyltransferase 2 (KMT2) family of proteins, which currently consists of at least 5 members, methylate lysine 4 on the histone H3 tails at important regulatory regions in the genome and thereby impart crucial functions through the modulation of chromatin structures and DNA accessibility (Morera, Lübbert, and Jung., Clin. Epigenetics 8, 57- (2016)). These enzymes are known to play an important role in the regulation of gene expression during early development and hematopoiesis (Rao & Dou., Nat.Rev. Cancer 15, 334-346 (2015)).

The human KMT2 family was initially named the mixed-lineage leukaemia (MLL) family, owing to the role of the first-found member in this disease, KMT2A which is still commonly referred to as MLL1 or MLL in routine clinical practice.

KMT2A (MLL1) is frequently found to be cytogenetically targeted in several types of leukemia (e.g. ALL and AML), and in those cases where balanced chromosomal translocations are found, these typically target KMT2A (MLL1) and one of over 80 translocation partner genes that have been described to date (Winters and Bernt, Front. Pediatr. 5, 4 (2017)). These chromosomal anomalies often result in the formation of fusion genes that encode fusion proteins which are believed to be causally related to the onset and/or progression of the disease.

Leukemia-associated Mll fusion proteins typically contain functional MLL1 protein domains residing upstream of the breakpoint cluster region, including the Menin binding domain (MBD), a set of 3 so-called AT-hooks, which are known to bind to AT-rich DNA in a rather a-specific manner, two SNL or Speckled Nuclear Localization Signals, which target the protein to the nucleus, and two Repression Domains (RD) which contain a single CXXC Zinc Finger Domain known to be binding umethylated CpG DNA (Winters and Bernt, Front. Pediatr. 5, 4 (2017), Ballabio and Milne, Cancer 4, 904-944 (2012)).

Several proteins have been identified that are capable of interacting with some of the above functional domains. Among these, proteins that are known to be involved in the activation of MLL (KMT2A)-dependent transcription include Menin (which, in turn, interacts with LEDGF) and PAFc.

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